Research ArticleExperimental Studies

Brexpiprazole Reduces Survivin and Reverses EGFR Tyrosine Kinase Inhibitor Resistance in Lung and Pancreatic Cancer

TOMOMI SANOMACHI, SHUHEI SUZUKI, KEITA TOGASHI, SHIZUKA SEINO, TAKASHI YOSHIOKA, CHIFUMI KITANAKA, MASASHI OKADA and MASAHIRO YAMAMOTO
Anticancer Research September 2019, 39 (9) 4817-4828; DOI: https://doi.org/10.21873/anticanres.13667

Abstract

Background/Aim: Although epidermal growth factor receptor (EGFR) is frequently activated in lung and pancreatic cancers, the efficacy of EGFR tyrosine kinase inhibitors (EGFR-TKIs) is limited. Recently, brexpiprazole, an antipsychotic drug, was reported to chemosensitize glioma cells to osimertinib, a third-generation EGFR-TKI, by suppressing survivin, an anti-apoptotic protein, but their combinational effects on lung and pancreatic cancers remain unknown. The aim of this study was to examine the combinational effects of brexpiprazole and osimertinib on lung and pancreatic cancer cells in vitro and in vivo. Materials and Methods: YM155, a suppressor of survivin, siRNA, and immunoblot were used to examine the role of survivin in osimertinib-resistance. The effect of drugs on cell viability in vitro was examined by trypan blue staining. The in vivo effects of drugs on tumor growth were examined using a xenograft mouse model. Results: Brexpiprazole exerted combinational effects with osimertinib in vitro. Pharmacological and genetic suppression of survivin chemosensitized the cells to osimertinib. Moreover, the combination of brexpiprazole and osimertinib effectively suppressed tumor growth in a mouse xenograft model. Conclusion: Brexpiprazole is a promising drug for lung and pancreatic cancer in combination with osimertinib.

The epidermal growth factor receptor (EGFR) pathway is activated by gene mutation, gene amplification, or both in several types of cancer, including non-small-cell lung cancer (NSCLC), pancreatic cancer, glioblastoma, colorectal cancer, breast cancer, and squamous cell carcinoma of the head and neck (1, 2). The activation of the EGFR pathway functions in the development and progression of cancer. Therefore, it is one of the targets of cancer chemotherapy using EGFR tyrosine kinase inhibitors (EGFR-TKIs), anti-EGFR antibodies, or immunotherapy against EGFR.

In NSCLC, activation mutations of the EGFR gene are detected in ~15-20% of cases (3, 4). The majority of NSCLC harbors the wild-type EGFR gene, but it is primarily resistant to EGFR-TKIs (5, 6). Although previous studies, including ours, have identified potential chemosensitizers of EGFR-TKIs in wild-type EGFR NSCLC, they have not reached clinical use (7-9). Thus, chemosensitizers to overcome the primary resistance to EGFR-TKIs in wild-type EGFR NSCLC are required. On the other hand, for patients with mutant EGFR NSCLC, first-generation EGFR-TKIs (gefitinib and erlotinib) are used as the first-line treatment. However, long-term treatment with EGFR-TKIs causes secondary resistance by several mechanisms, including the T790M resistance mutation, which is the most common mechanism of resistance, in approximately 50% of patients treated with first-generation EGFR-TKIs (10). Osimertinib, an oral, third-generation, irreversible EGFR-TKI, was developed to overcome resistance mediated by the T790M EGFR mutation (11, 12). In the phase III FLAURA trial, the efficacy and tolerability of osimertinib were found to be superior to those of standard EGFR-TKIs as first-line treatment for NSCLC, and osimertinib is currently recommended as first-line treatment (13). However, acquired resistance against osimertinib may develop and prevent an optimal outcome (14). Thus, chemosensitizers that overcome the acquired resistance to osimertinib in mutant EGFR-NSCLC are required.

EGFR-TKIs are also used for patients with pancreatic cancer. In pancreatic cancer, EGFR is overexpressed, and therapy targeting EGFR has been reported as promising (15, 16). Indeed, in a phase III clinical trial, erlotinib combined with gemcitabine improved the clinical outcome compared with gemcitabine alone (17-19). However, the prognosis of pancreatic cancer is poor. Therefore, reagents that augment the effects of EGFR-TKIs in pancreatic cancer are needed. As osimertinib has a better toxicity profile than standard EGFR-TKIs in clinical studies (12, 13), osimertinib is a candidate EGFR-TKI for pancreatic cancer.

Brexpiprazole is a novel agent for depression and schizophrenia (20-22). Brexpiprazole was developed as a successor to aripiprazole, a dopamine-serotonin activity modulator with anti-cancer activity (23). Although the chemical and pharmacological properties of brexpiprazole are similar to those of aripiprazole, brexpiprazole has a better toxicity profile because of its lower intrinsic activity at D2 and D3 dopaminergic receptors (21, 24). We have recently revealed that, similar to aripiprazole, brexpiprazole has anti-cancer effects and acts as a chemosensitizer to 5-fluorouracil and gemcitabine in stem cells of NSCLC and pancreatic cancer (25). Moreover, we have previously reported that brexpiprazole chemosensitizes glioma stem cells, cancer stem cells of glioblastoma, to osimertinib by downregulating the expression of survivin, an anti-apoptotic protein (26). These results suggest that brexpiprazole acts as a chemosensitizer of osimertinib in other types of malignancies. However, it remains unclear whether the endogenous expression of survivin plays a major role in osimertinib resistance in NSCLC and pancreatic cancer, and whether brexpiprazole augments the effects of osimertinib through survivin suppression in these cancers. Thus, in this study, we explored the role of brexpiprazole as a chemosensitizer to osimertinib in wild-type EGFR NSCLC cells, osimertinib-resistant mutant EGFR NSCLC cells, and pancreatic cancer cells in vitro and in vivo, and examined the involvement of survivin in the osimertinib resistance mechanism.

Materials and Methods

Antibodies and reagents. Anti-β-actin (A1978) antibody was purchased from Sigma (St. Louis, MO, USA). Anti-survivin (#2808) antibody was from Cell Signaling Technology, Inc. (Beverly, MA, USA). Osimertinib and YM155 were purchased from Chemscene LLC. (Monmouth Junction, NJ, USA) and dissolved in dimethyl sulfoxide (DMSO) to 10 mM and 20 μM stock solutions, respectively. Brexpiprazole was from Cayman Chemical Company (Ann Arbor, MI, USA) and was dissolved in DMSO to 10 mM stock solution.

Cell culture and in vitro generation of an osimertinib-resistant cell line. Human non-small cell lung cancer (NSCLC) cell lines A549 and PC-9 were obtained from the Riken BioResource Center (Tsukuba, Japan). The human pancreatic cell line PANC-1 was from the Cell Resource Center for Biomedical Research, Institute of Development, Aging and Cancer, Tohoku University (Sendai, Japan). These cell lines were cultured in DMEM/F12 medium supplemented with 10% fetal bovine serum, 100 units/ml of penicillin, and 100 μg/ml of streptomycin as serum-cultured non-stem cancer cells. The establishment of cancer stem cells, A549 CSLC and PANC-1 CSLC cells, have been previously reported (27-30). The authenticity of A549 CSLC and PANC-1 CSLC cells was confirmed by genotyping of short tandem repeat (STR) loci (Bio-Synthesis, Inc., Lewisville, TX, USA) and comparing with the ATCC STR database for Human Cell Lines. These cancer stem cells were cultured, as previously described (28, 30, 31), on collagen I-coated dishes (IWAKI, Tokyo, Japan) in stem cell culture medium [DMEM/F12 medium with 1% B27 supplement (Thermo Fisher Scientific, Waltham, MA, USA), 20 ng/ml of EGF and FGF2 (Peprotech, Inc., Rocky Hill, NJ, USA), D-(+)-glucose (final concentration, 26.2 mM), L-glutamine (final concentration, 4.5 mM), 100 units/ml of penicillin, and 100 μg/ml of streptomycin]. The stem cell culture medium was changed every 3 days, and EGF and FGF2 were supplemented in the medium every day. An osimertinib-resistant subline of PC-9 (PC-9-OR) was established by culturing in the presence of increasing concentrations of osimertinib (0.1-1.5 μM) over a two-month period. PC-9-OR cells were maintained in the presence of 1.5 μM osimertinib.

Cell viability assays. Viable and dead cells were identified by their ability and inability to exclude vital dyes, respectively (23, 30, 32). In short, harvested cells were stained with 0.2% trypan blue as a vital dye, and the numbers of viable and dead cells were counted using a hemocytometer. The percent of dead cells (%) was defined as 100× ‘the number of dead cells’/(‘the number of viable cells’ + ‘the number of dead cells’).

Immunoblot analysis. Cells or tumors were washed with PBS and lysed in RIPA buffer [10 mM Tris-HCl (pH 7.4), 0.1% SDS, 0.1% sodium deoxycholate, 1% NP-40, 150 mM NaCl, 1 mM EDTA, 1.5 mM Na3VO4, 10 mM NaF, 10 mM sodium pyrophosphate, 10 mM sodium β-glycerophosphate, and 1% protease inhibitor cocktail set III (Sigma)]. After centrifugation for 10 min at 14,000 × g at 4°C, the supernatants were harvested as the cell lysates, and the protein concentration of cell lysates was measured using a BCA protein assay kit (Thermo Fisher Scientific). Cell lysates containing equal amounts of protein were separated by SDS-PAGE and transferred to polyvinylidene difluoride membranes. The membranes were probed with primary antibodies followed by an appropriate HRP-conjugated secondary antibody according to the manufacturer's instructions. The immunoreactive bands were visualized using Immobilon Western Chemiluminescent HRP Substrate (Merck Millipore, Darmstadt, Germany) and ChemiDoc Touch Imaging System (Bio-Rad, Hercules, CA, USA).

Gene silencing by siRNA. siRNAs against human survivin (BIRC5 #2; HSS 179404, #3; HSS 179405) and Medium GC Duplex #2 of Stealth RNAi™ siRNA Negative Control Duplexes (non-targeting) were purchased from Thermo Fisher Scientific. Cells were transiently transfected with RNAs using Lipofectamine RNAiMAX™ (Thermo Fisher Scientific).

Mouse study. Mouse xenograft studies were carried out as previously described (28, 33). After anesthetization (intraperitoneal injection of medetomidine, midazolam, and butorphanol at 0.3 mg, 4 mg, and 5 mg per kg of body weight, respectively), A549 cells (1×106) suspended in 200 μl PBS were implanted subcutaneously in the flank region of 7-week-old male BALB/cAJcl-nu/nu mice (CLEA Japan, Inc., Tokyo, Japan). The tumor volume was assessed by measuring tumor diameters using calipers and calculated as the larger diameter × smaller diameter × height. For systemic administration of drugs, stock solutions of brexpiprazole (4 mg/ml) and osimertinib (2 mg/ml) were diluted in DMSO to prepare 100-μl solutions for each injection, respectively. Brexpiprazole was administered by oral gavage to mice at 3 mg/kg twice a week and osimertinib was orally administered at 5 mg/kg five times a week. Drug treatment started 6 days after tumor implantation and confirmation of subcutaneous tumor formation, and tumor-bearing mice were randomized into four groups before the initiation of drug treatment. All animal experiment protocols were approved by the Animal Research Committee of Yamagata University.

Statistical analysis. The results are expressed as the means and standard deviation (SD). The differences were compared using the two-tailed t-test. p-Values < 0.05 were considered significant and indicated with asterisks.

Results

Brexpiprazole sensitizes serum-cultured cancer cells and cancer stem cells of NSCLC and pancreatic cancer to osimertinib. First, the effects of co-treatment with brexpiprazole and osimertinib were examined. The representative NSCLC cell lines were: A549, which harbors wild-type EGFR, and PC-9-OR, which is a subline established by culturing PC-9 cells harboring a EGFR-TKI-sensitive mutated EGFR gene with osimertinib (acquired resistance); the representative pancreatic cell line was PANC-1. Although the concentration of osimertinib used in the experiments (2 μM) was sufficiently high to suppress the growth of osimertinib-sensitive PC-9 cells [data not shown and references (34, 35)], their growth was suppressed only mildly (Figure 1A), suggesting that these cells were resistant to osimertinib. Compared with osimertinib or brexpiprazole alone, co-treatment with osimertinib and brexpiprazole significantly reduced the cell number and increased cell death in these serum-cultured non-stem cancer cells (Figure 1A). Since we have previously reported that brexpiprazole sensitizes glioma stem cells to osimertinib (26), we examined whether brexpiprazole reduces osimertinib resistance in cancer stem cells of NSCLC and pancreatic cancer. Co-treatment with brexpiprazole and osimertinib significantly reduced the number of viable cells and increased death of cancer stem cells (Figure 2A).

Brexpiprazole reduces endogenous expression of survivin in NSCLC and pancreatic cancer cells, which is essential for their osimertinib resistance. Reduction of the expression of survivin, an anti-apoptotic protein, has been reported to sensitize cancer cells to EGFR-TKIs (36-39), and we have recently demonstrated that brexpiprazole reduces the expression of survivin in serum-cultured cancer cells, including A549 and PANC-1 cells, and cancer stem cells, including A549 CSLC and PANC-1 CSLC cells (25). Thus, we examined the expression of survivin in the serum-cultured cancer cells and cancer stem cells of NSCLC and pancreatic cancer that were treated with brexpiprazole at the concentration that induces sensitization. Brexpiprazole reduced the expression of survivin in these cells (Figure 1B and 2B).

To assess whether the expression of survivin plays a role in osimertinib resistance in these cells, we next examined whether YM155, a pharmacological inhibitor of survivin (40, 41), sensitizes these cells to osimertinib. After confirmation of the reduction of survivin expression by YM155 (Figure 3A), the osimertinib-resistant cell lines were co-treated with osimertinib and YM155. YM155 was found to sensitize these cell lines to osimertinib to a degree similar to that of brexpiprazole (Figure 3B). Moreover, to exclude the possibility of unintentional off-target effects of YM155, we investigated the effects of genetic downregulation of survivin by siRNA on the sensitivity to osimertinib in the resistant cell lines. After confirmation of the downregulating effects of two siRNAs (Figure 4A), the osimertinib-resistant cell lines were administered siRNAs against survivin and then treated with osimertinib. Suppression of survivin by siRNAs attenuated osimertinib resistance of osimertinib-resistant cell lines (Figure 4B). Together, these results demonstrate that the endogenous expression of survivin is an essential factor determining cellular resistance to osimertinib, and suggest that brexpiprazole sensitizes NSCLC and pancreatic cancer cells to osimertinib, at least in part, through the downregulation of survivin expression.

Brexpiprazole attenuates osimertinib-resistance in vivo. The above described results suggested that survivin inhibition effectively reverses the resistance to osimertinib in NSCLC and pancreatic cancer cell lines in vitro. In order to examine the therapeutic relevance of these in vitro findings in vivo, we evaluated the efficacy of co-treatment with osimertinib and brexpiprazole against the wild-type EGFR NSCLC cell line A549. After confirming the formation of tumors following implantation of A549 into nude mice, both osimertinib and brexpiprazole were repeatedly orally administered. As a result, tumor growth was significantly inhibited by the combination of osimertinib and brexpiprazole (Figure 5A). Although the mice that received osimertinib and brexpiprazole lost weight at the beginning of treatment, their body weight later recovered to a level similar to that of the other groups (Figure 5B). No adverse effects were observed. We also examined whether brexpiprazole reduces the expression of survivin in vivo, and found that its expression in the tumors was decreased (Figure 5C).

Figure 1.
Figure 1.

Brexpiprazole sensitizes serum-cultured cancer cells to osimertinib. Serum-cultured cancer cells were incubated with or without 2 μM osimertinib and with or without brexpiprazole for 3 days (brexpiprazole concentration was 2.5 μM for A549 and PANC-1, and 1.5 μM for PC-9-OR), and then subjected to cell viability assay using trypan blue (A). The initial number of A549 and PANC-1 cells was 5×104 and that of PC-9-OR cells was 1×105. The total number of cells (viable and dead) (left panels) and the percentage of dead cells (right panels) are shown. Values represent means±SD from quadruplicate samples of a representative experiment repeated three times with similar results. *p<0.05. In the left panels, the number of viable cells was compared. Serum-cultured cancer cells were incubated with or without brexpiprazole (brexpiprazole concentration was 2.5 μM for A549 and PANC-1, and 1.5 μM for PC-9-OR) for 3 days, and then subjected to immunoblot analysis of survivin (B).

Discussion

As EGFR signaling is activated in several types of cancers, the effectiveness of therapies targeting EGFR has been clinically confirmed. However, their effectiveness is sometimes poor or limited because of primary or acquired resistance (42). Although several studies have been performed to find methods to overcome this resistance, such therapies have not reached clinical use. In this study, we found that brexpiprazole, a novel serotonin-dopamine activity modulator with an excellent safety profile, sensitized wild-type EGFR and osimertinib-resistant NSCLC and pancreatic cancer, which have intrinsic or acquired resistance, to osimertinib in vitro and in vivo. As brexpiprazole is currently clinically used for schizophrenia and depression with a known safety profile, our study suggests that it is a promising candidate chemosensitizer to osimertinib for EGFR-TKI-resistant cancers.

Several studies targeting EGFR-TKI resistance have been reported. For wild-type EGFR NSCLC, the therapeutic effects of erlotinib are increased by the inhibition of GLUT1 (8), restoration of the TUSC gene (43), inhibition of MER proto-oncogene protein tyrosine kinase (MERTK) (9), and pre-treatment by cisplatin-based chemotherapy (44). However, these strategies have not been clinically applied. Regarding mutant EGFR NSCLC, osimertinib was originally developed to overcome the T790M mutation of EGFR that confers resistance to first- and second-generation EGFR-TKIs, but resistance to osimertinib is also acquired during treatment (11, 45). The mechanisms of the acquired resistance to osimertinib include loss of the T790M mutation, mutation of EGFR, such as C797S mutation, activation of bypassing pathways: HER2 amplification, MET amplification, PIK3CA activation mutation, up-regulation of AXL, and histological transition by small cell transformation or epithelial-mesenchymal transition (45-47). Although preclinical studies to overcome osimertinib resistance have been performed (47-50), a standard therapy for osimertinib-resistant mutant EGFR NSCLC has not been established (14, 46). For pancreatic cancer, preclinical and clinical studies to improve the effects of erlotinib have been carried out, but their results have not been applied for clinical use (51-54). Survivin, a member of the inhibitor of apoptosis protein family, mediates the resistance to EGFR-TKI in NSCLC, and its suppression indeed chemosensitizes NSCLC cells to erlotinib (36-39). However, it remains to be demonstrated whether inhibiting survivin expression is a viable approach to chemosensitize cancer cells to osimertinib. In this study, we confirmed that genetic and pharmacological inhibition of survivin expression sensitized NSCLC and pancreatic cancer cells, which have intrinsic or acquired osimertinib resistance, to osimertinib, and that brexpiprazole, which reduced survivin expression in these cells, effectively sensitized them to osimertinib. These results suggested that survivin is, at least in part, one of the major factors in osimertinib resistance, and that its suppression prevents different resistant mechanisms in NSCLC and pancreatic cancer cells.

Figure 2.
Figure 2.

Brexpiprazole sensitizes cancer stem cells to osimertinib. Cancer stem cells were cultured with or without 2 μM osimertinib and with or without 2.5 μM brexpiprazole for 3 days, and then subjected to cell viability assay using trypan blue (A). The initial cell number was 1×105 cells for both A549 CSLC and PANC-1 CSLC. The total number of (viable and dead) (left panels) and the percentage of dead cells (right panels) are shown. Values represent means±SD from quadruplicate samples of a representative experiment repeated three times with similar results. *p<0.05. In the left panels, the number of viable cells was compared. Cancer stem cells were cultured with or without 2.5 μM brexpiprazole for 3 days, and then subjected to immunoblot analysis of survivin (B).

As survivin has been implicated in chemoresistance in cancer, it is regarded as a promising target for cancer therapy (55). Survivin is targeted by several strategies such as small molecule inhibitors, transcriptional suppression by antisense oligonucleotide, or RNA interference (56). Although clinical trials targeting survivin have been performed, the efficacy of these therapies has not been confirmed or is only limited (57). YM155, a small molecule that pharmacologically inhibits survivin, exhibits a favorable safety tolerability profile (58). However, clinical trials using YM155 are insufficient and there are many unknown factors (59-61). LY2181308, a survivin antisense oligonucleotide, has exhibited a favorable toxicity profile in a phase I clinical trial (62). However, its efficacy was not confirmed in a randomized phase II clinical trial for castration-resistant prostate cancer (63). From the perspective of drug repurposing, we have previously demonstrated that clinically used antipsychotics, olanzapine and aripiprazole, reduce survivin expression (23, 32), but olanzapine may cause deep sedation (64) and aripiprazole causes akathisia (20, 21). Moreover, cancer patients are frail and sensitive to medications due to insufficient kidney and liver functions. Brexpiprazole is better than aripiprazole because it has fewer side effects such as akathisia and extrapyramidal symptoms (21, 24). Brexpiprazole is used as an antipsychotic and antidepressant (65, 66), and thus may be effective from the standpoint of psycho-oncology. Additionally, it is widely used worldwide and has been approved by the Food and Drug Administration. Therefore, it can be promptly adapted to clinical settings.

Figure 3.
Figure 3.

Pharmacological survivin inhibition by YM155 sensitizes osimertinib-resistant cells to osimertinib. The indicated serum-cultured cancer cells and cancer stem cells were cultured with or without 10 nM YM155 (only for PC-9-OR 3 nM) and with or without 2 μM osimertinib for 3 days. (A), extracts of cells treated with or without YM155 only were subjected to immunoblot analysis of survivin expression. (B) Cells were subjected to cell viability assay using trypan blue. The initial number of A549 and PANC-1 cells was 5×104 and that of PC-9-OR, A549 CSLC, and PANC-1 CSLC cells was 1×105 cells. Values represent means±SD from triplicate samples of a representative experiment repeated three times with similar results. *: p<0.05 (comparing viable cells).

Figure 4.
Figure 4.

siRNA knockdown of survivin sensitizes osimertinib-resistant cancer cells to osimertinib. Non-targeting siRNA (siControl) or either of the siRNAs against survivin (siSurvivin#2 or siSurvivin#3) were introduced to the indicated serum-cultured cancer cells or cancer stem cells for 3 days. (A), cell extracts were subjected to immunoblot analysis of survivin expression. (B) Transfected cells were cultured with or without 2 μM osimertinib for 3 days, and were then subjected to cell viability assay using trypan blue. The initial number of A549 and PANC-1 cells was 5×104 and that of PC-9-OR, A549 CSLC, and PANC-1 CSLC cells was 1×105. Values represent means±SD from triplicate samples of a representative experiment repeated three times with similar results. *p<0.05 (comparing viable cells).

Figure 5.
Figure 5.

Dual administration of brexpiprazole and osimertinib reduces osimertinib-resistance in vivo. Wild-type EGFR NSCLC cells (A549, 1×106 cells) were subcutaneously implanted into the trunk of nude mice. After confirming tumor formation, the indicated drugs (3 mg/kg of brexpiprazole twice a week, 5 mg/kg of osimertinib 5 times a week, or both) were orally administered. (A), the tumor volume of each group is shown (n=8, each group). (B). The body weight of the mice is presented. (C). The tumor tissues excised from the control and brexpiprazole-treated mice were subjected to immunoblot analysis of survivin. *p<0.05, comparison at the end of the study.

In this study, we showed that the endogenous expression of survivin is a major factor in osimertinib resistance in wild-type and mutant EGFR NSCLC, and pancreatic cancer, and that brexpiprazole chemosensitizes these cancer cells to osimertinib, most likely through suppression of survivin expression. In conclusion, brexpiprazole is a promising drug in combination with osimertinib to treat NSCLC or pancreatic cancer.

Acknowledgements

This study was supported by Grants-in-Aid for Scientific Research, for Challenging Exploratory Research, and for Young Scientists from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

Footnotes

  • ↵* These Authors contributed equally to this work.

  • Authors' Contributions

    T.S., S. Suzuki, C.K., M.O., and M.Y. designed the research. T.S., S. Suzuki, and S. Seino performed the experiments. T.S., S. Suzuki, M.O., and M.Y. wrote the original paper, and T.S., S. Suzuki, K.T., S. Shizuka, T.Y. C.K., M.O., and M.Y. reviewed and edited paper. All Authors discussed the results and contributed to the final manuscript.

  • Conflicts of Interest

    The Authors declare no conflicts of interest regarding this study.

  • Received August 8, 2019.
  • Revision received August 14, 2019.
  • Accepted August 15, 2019.

References

  1. ↵
    1. Yarden Y,
    2. Pines G
    : The ERBB network: at last, cancer therapy meets systems biology. Nat Rev Cancer 12(8): 553-563, 2012. PMID: 22785351. DOI: 10.1038/nrc3309
    OpenUrlCrossRefPubMed
  2. ↵
    1. Sigismund S,
    2. Avanzato D,
    3. Lanzetti L
    : Emerging functions of the EGFR in cancer. Mol Oncol 12(1): 3-20, 2018. PMID: 29124875. DOI: 10.1002/1878-0261.12155
    OpenUrlCrossRefPubMed
  3. ↵
    1. Yun CH,
    2. Boggon TJ,
    3. Li Y,
    4. Woo MS,
    5. Greulich H,
    6. Meyerson M,
    7. Eck MJ
    : Structures of lung cancer-derived EGFR mutants and inhibitor complexes: mechanism of activation and insights into differential inhibitor sensitivity. Cancer Cell 11(3): 217-227, 2007. PMID: 17349580. DOI: 10.1016/j.ccr.2006.12.017
    OpenUrlCrossRefPubMed
  4. ↵
    1. Cancer Genome Atlas Research N
    : Comprehensive molecular profiling of lung adenocarcinoma. Nature 511(7511): 543-550, 2014. PMID: 25079552. DOI: 10.1038/nature13385
    OpenUrlCrossRefPubMed
  5. ↵
    1. Paez JG,
    2. Janne PA,
    3. Lee JC,
    4. Tracy S,
    5. Greulich H,
    6. Gabriel S,
    7. Herman P,
    8. Kaye FJ,
    9. Lindeman N,
    10. Boggon TJ,
    11. Naoki K,
    12. Sasaki H,
    13. Fujii Y,
    14. Eck MJ,
    15. Sellers WR,
    16. Johnson BE,
    17. Meyerson M
    : EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 304(5676): 1497-1500, 2004. PMID: 15118125. DOI: 10.1126/science.1099314
    OpenUrlAbstract/FREE Full Text
  6. ↵
    1. Zhu CQ,
    2. da Cunha Santos G,
    3. Ding K,
    4. Sakurada A,
    5. Cutz JC,
    6. Liu N,
    7. Zhang T,
    8. Marrano P,
    9. Whitehead M,
    10. Squire JA,
    11. Kamel-Reid S,
    12. Seymour L,
    13. Shepherd FA,
    14. Tsao MS,
    15. National Cancer Institute of Canada Clinical Trials Group Study BR
    : Role of KRAS and EGFR as biomarkers of response to erlotinib in National Cancer Institute of Canada Clinical Trials Group Study BR.21. J Clin Oncol 26(26): 4268-4275, 2008. PMID: 18626007. DOI: 10.1200/JCO.2007.14.8924
    OpenUrlAbstract/FREE Full Text
  7. ↵
    1. Li YL,
    2. Hu X,
    3. Li QY,
    4. Wang F,
    5. Zhang B,
    6. Ding K,
    7. Tan BQ,
    8. Lin NM,
    9. Zhang C
    : Shikonin sensitizes wildtype EGFR NSCLC cells to erlotinib and gefitinib therapy. Mol Med Rep 18(4): 3882-3890, 2018. PMID: 30106133. DOI: 10.3892/mmr. 2018.9347
    OpenUrlPubMed
  8. ↵
    1. Suzuki S,
    2. Okada M,
    3. Takeda H,
    4. Kuramoto K,
    5. Sanomachi T,
    6. Togashi K,
    7. Seino S,
    8. Yamamoto M,
    9. Yoshioka T,
    10. Kitanaka C
    : Involvement of GLUT1-mediated glucose transport and metabolism in gefitinib resistance of non-small-cell lung cancer cells. Oncotarget 9(66): 32667-32679, 2018. PMID: 30220973. DOI: 10.18632/oncotarget.25994
    OpenUrlPubMed
  9. ↵
    1. Yan D,
    2. Parker RE,
    3. Wang X,
    4. Frye SV,
    5. Earp HS 3rd.,
    6. DeRyckere D,
    7. Graham DK
    : MERTK promotes resistance to irreversible EGFR tyrosine kinase inhibitors in non-small cell lung cancers expressing wild-type EGFR family members. Clin Cancer Res 24(24): 6523-6535, 2018. PMID: 30194074. DOI: 10.1158/1078-0432.CCR-18-0040
    OpenUrlAbstract/FREE Full Text
  10. ↵
    1. Kobayashi S,
    2. Boggon TJ,
    3. Dayaram T,
    4. Janne PA,
    5. Kocher O,
    6. Meyerson M,
    7. Johnson BE,
    8. Eck MJ,
    9. Tenen DG,
    10. Halmos B
    : EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med 352(8): 786-792, 2005. PMID: 1572 8811. DOI: 10.1056/NEJMoa044238
    OpenUrlCrossRefPubMed
  11. ↵
    1. Janne PA,
    2. Yang JC,
    3. Kim DW,
    4. Planchard D,
    5. Ohe Y,
    6. Ramalingam SS,
    7. Ahn MJ,
    8. Kim SW,
    9. Su WC,
    10. Horn L,
    11. Haggstrom D,
    12. Felip E,
    13. Kim JH,
    14. Frewer P,
    15. Cantarini M,
    16. Brown KH,
    17. Dickinson PA,
    18. Ghiorghiu S,
    19. Ranson M
    : AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. N Engl J Med 372(18): 1689-1699, 2015. PMID: 25923549. DOI: 10.1056/NEJMo a1411817
    OpenUrlCrossRefPubMed
  12. ↵
    1. Mok TS,
    2. Wu YL,
    3. Ahn MJ,
    4. Garassino MC,
    5. Kim HR,
    6. Ramalingam SS,
    7. Shepherd FA,
    8. He Y,
    9. Akamatsu H,
    10. Theelen WS,
    11. Lee CK,
    12. Sebastian M,
    13. Templeton A,
    14. Mann H,
    15. Marotti M,
    16. Ghiorghiu S,
    17. Papadimitrakopoulou VA,
    18. Investigators A
    : Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer. N Engl J Med 376(7): 629-640, 2017. PMID: 27959700. DOI: 10.1056/NEJMoa1612674
    OpenUrlCrossRefPubMed
  13. ↵
    1. Soria JC,
    2. Ohe Y,
    3. Vansteenkiste J,
    4. Reungwetwattana T,
    5. Chewaskulyong B,
    6. Lee KH,
    7. Dechaphunkul A,
    8. Imamura F,
    9. Nogami N,
    10. Kurata T,
    11. Okamoto I,
    12. Zhou C,
    13. Cho BC,
    14. Cheng Y,
    15. Cho EK,
    16. Voon PJ,
    17. Planchard D,
    18. Su WC,
    19. Gray JE,
    20. Lee SM,
    21. Hodge R,
    22. Marotti M,
    23. Rukazenkov Y,
    24. Ramalingam SS,
    25. Investigators F
    : Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N Engl J Med 378(2): 113-125, 2018. PMID: 29151359. DOI: 10.1056/NEJMoa 1713137
    OpenUrlCrossRefPubMed
  14. ↵
    1. Murtuza A,
    2. Bulbul A,
    3. Shen JP,
    4. Keshavarzian P,
    5. Woodward BD,
    6. Lopez-Diaz FJ,
    7. Lippman SM,
    8. Husain H
    : Novel thirdgeneration EGFR tyrosine kinase inhibitors and strategies to overcome therapeutic resistance in lung cancer. Cancer Res 79(4): 689-698, 2019. PMID: 30718357. DOI: 10.1158/0008-5472.CAN-18-1281
    OpenUrlAbstract/FREE Full Text
  15. ↵
    1. Ueda S,
    2. Ogata S,
    3. Tsuda H,
    4. Kawarabayashi N,
    5. Kimura M,
    6. Sugiura Y,
    7. Tamai S,
    8. Matsubara O,
    9. Hatsuse K,
    10. Mochizuki H
    : The correlation between cytoplasmic overexpression of epidermal growth factor receptor and tumor aggressiveness: poor prognosis in patients with pancreatic ductal adenocarcinoma. Pancreas 29(1): e1-8, 2004. PMID: 15211117.
    OpenUrlCrossRefPubMed
  16. ↵
    1. Lee J,
    2. Jang KT,
    3. Ki CS,
    4. Lim T,
    5. Park YS,
    6. Lim HY,
    7. Choi DW,
    8. Kang WK,
    9. Park K,
    10. Park JO
    : Impact of epidermal growth factor receptor (EGFR) kinase mutations, EGFR gene amplifications, and KRAS mutations on survival of pancreatic adenocarcinoma. Cancer 109(8): 1561-1569, 2007. PMID: 17354229. DOI: 10.1002/cncr.22559
    OpenUrlCrossRefPubMed
  17. ↵
    1. Moore MJ,
    2. Goldstein D,
    3. Hamm J,
    4. Figer A,
    5. Hecht JR,
    6. Gallinger S,
    7. Au HJ,
    8. Murawa P,
    9. Walde D,
    10. Wolff RA,
    11. Campos D,
    12. Lim R,
    13. Ding K,
    14. Clark G,
    15. Voskoglou-Nomikos T,
    16. Ptasynski M,
    17. Parulekar W
    : Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 25(15): 1960-1966, 2007. PMID: 17452677. DOI: 10.1200/jco.2006.07.9525
    OpenUrlAbstract/FREE Full Text
    1. Okusaka T,
    2. Furuse J,
    3. Funakoshi A,
    4. Ioka T,
    5. Yamao K,
    6. Ohkawa S,
    7. Boku N,
    8. Komatsu Y,
    9. Nakamori S,
    10. Iguchi H,
    11. Ito T,
    12. Nakagawa K,
    13. Nakachi K
    : Phase II study of erlotinib plus gemcitabine in Japanese patients with unresectable pancreatic cancer. Cancer Sci 102(2): 425-431, 2011. PMID: 21175992. DOI: 10.1111/j.1349-7006.2010.01810.x
    OpenUrlCrossRefPubMed
  19. ↵
    1. Yang ZY,
    2. Yuan JQ,
    3. Di MY,
    4. Zheng DY,
    5. Chen JZ,
    6. Ding H,
    7. Wu XY,
    8. Huang YF,
    9. Mao C,
    10. Tang JL
    : Gemcitabine plus erlotinib for advanced pancreatic cancer: a systematic review with meta-analysis. PLoS One 8(3): e57528, 2013. PMID: 23472089. DOI: 10.1371/journal.pone.0057528
    OpenUrlCrossRefPubMed
  20. ↵
    1. Aladeen T,
    2. Westphal E,
    3. Lee Y,
    4. Rong C,
    5. Rainka M,
    6. Capote H,
    7. McIntyre RS
    : The use of brexpiprazole amongst individuals with insufficient outcomes with aripiprazole or bupropion: A case series. Perspect Psychiatr Care 54(4): 507-513, 2018. PMID: 29427512. DOI: 10.1111/ppc.12258
    OpenUrlPubMed
  21. ↵
    1. Frankel JS,
    2. Schwartz TL
    : Brexpiprazole and cariprazine: distinguishing two new atypical antipsychotics from the original dopamine stabilizer aripiprazole. Ther Adv Psychopharmacol 7(1): 29-41, 2017. PMID: 28101322. DOI: 10.1177/20451 25316672136
    OpenUrlPubMed
  22. ↵
    1. Correll CU,
    2. Skuban A,
    3. Ouyang J,
    4. Hobart M,
    5. Pfister S,
    6. McQuade RD,
    7. Nyilas M,
    8. Carson WH,
    9. Sanchez R,
    10. Eriksson H
    : Efficacy and safety of brexpiprazole for the treatment of acute schizophrenia: a 6-week randomized, double-blind, placebo-controlled trial. Am J Psychiatry 172(9): 870-880, 2015. PMID: 25882325. DOI: 10.1176/appi.ajp.2015.14101275
    OpenUrlCrossRefPubMed
  23. ↵
    1. Suzuki S,
    2. Okada M,
    3. Kuramoto K,
    4. Takeda H,
    5. Sakaki H,
    6. Watarai H,
    7. Sanomachi T,
    8. Seino S,
    9. Yoshioka T,
    10. Kitanaka C
    : Aripiprazole, an antipsychotic and partial dopamine agonist, inhibits cancer stem cells and reverses chemoresistance. Anticancer Res 36(10): 5153-5161, 2016. PMID: 27798875. DOI: 10.21873/anticanres.11085
    OpenUrlAbstract/FREE Full Text
  24. ↵
    1. Citrome L,
    2. Ota A,
    3. Nagamizu K,
    4. Perry P,
    5. Weiller E,
    6. Baker RA
    : The effect of brexpiprazole (OPC-34712) and aripiprazole in adult patients with acute schizophrenia: results from a randomized, exploratory study. Int Clin Psychopharmacol 31(4): 192-201, 2016. PMID: 26963842. DOI: 10.1097/YIC.0000000 000000123
    OpenUrlPubMed
  25. ↵
    1. Suzuki S,
    2. Yamamoto M,
    3. Togashi K,
    4. Sanomachi T,
    5. Sugai A,
    6. Seino S,
    7. Yoshioka T,
    8. Kitanaka C,
    9. Okada M
    : In vitro and in vivo anti-tumor effects of brexpiprazole, a newly-developed serotonin-dopamine activity modulator with an improved safety profile. Oncotarget 10(37): 3547-3558, 2019. PMID: 31191825. DOI: 10.18632/oncotarget.26949
    OpenUrlCrossRefPubMed
  26. ↵
    1. Suzuki S,
    2. Yamamoto M,
    3. Sanomachi T,
    4. Togashi K,
    5. Sugai A,
    6. Seino S,
    7. Yoshioka T,
    8. Kitanaka C,
    9. Okada M
    : Brexpiprazole, a serotonin-dopamine activity modulator, can sensitize glioma stem cells to osimertinib, a third-generation EGFR-TKI, via survivin reduction. Cancers (Basel) 11(7), 2019. PMID: 31284441. DOI: 10.3390/cancers11070947
  27. ↵
    1. Gaviraghi M,
    2. Tunici P,
    3. Valensin S,
    4. Rossi M,
    5. Giordano C,
    6. Magnoni L,
    7. Dandrea M,
    8. Montagna L,
    9. Ritelli R,
    10. Scarpa A,
    11. Bakker A
    : Pancreatic cancer spheres are more than just aggregates of stem marker-positive cells. Biosci Rep 31(1): 45-55, 2011. PMID: 20426768. DOI: 10.1042/BSR20100018
    OpenUrlAbstract/FREE Full Text
  28. ↵
    1. Okada M,
    2. Shibuya K,
    3. Sato A,
    4. Seino S,
    5. Suzuki S,
    6. Seino M,
    7. Kitanaka C
    : Targeting the K-Ras--JNK axis eliminates cancer stem-like cells and prevents pancreatic tumor formation. Oncotarget 5(13): 5100-5112, 2014. PMID: 24947996. DOI: 10.18632/oncotarget.2087
    OpenUrlCrossRefPubMed
    1. Okada M,
    2. Shibuya K,
    3. Sato A,
    4. Seino S,
    5. Watanabe E,
    6. Suzuki S,
    7. Seino M,
    8. Kitanaka C
    : Specific role of JNK in the maintenance of the tumor-initiating capacity of A549 human non-small cell lung cancer cells. Oncol Rep 30(4): 1957-1964, 2013. PMID: 23912840. DOI: 10.3892/or.2013.2655
    OpenUrlCrossRefPubMed
  30. ↵
    1. Suzuki S,
    2. Okada M,
    3. Shibuya K,
    4. Seino M,
    5. Sato A,
    6. Takeda H,
    7. Seino S,
    8. Yoshioka T,
    9. Kitanaka C
    : JNK suppression of chemotherapeutic agents-induced ROS confers chemoresistance on pancreatic cancer stem cells. Oncotarget 6(1): 458-470, 2015. PMID: 25473894. DOI: 10.18632/oncotarget.2693
    OpenUrlCrossRefPubMed
  31. ↵
    1. Okada M,
    2. Kuramoto K,
    3. Takeda H,
    4. Watarai H,
    5. Sakaki H,
    6. Seino S,
    7. Seino M,
    8. Suzuki S,
    9. Kitanaka C
    : The novel JNK inhibitor AS602801 inhibits cancer stem cells in vitro and in vivo. Oncotarget 7(19): 27021-27032, 2016. PMID: 27027242. DOI: 10.18632/oncotarget.8395
    OpenUrlCrossRefPubMed
  32. ↵
    1. Sanomachi T,
    2. Suzuki S,
    3. Kuramoto K,
    4. Takeda H,
    5. Sakaki H,
    6. Togashi K,
    7. Seino S,
    8. Yoshioka T,
    9. Okada M,
    10. Kitanaka C
    : Olanzapine, an atypical antipsychotic, inhibits survivin expression and sensitizes cancer cells to chemotherapeutic agents. Anticancer Res 37(11): 6177-6188, 2017. PMID: 29061799. DOI: 10.21873/anticanres.12067
    OpenUrlAbstract/FREE Full Text
  33. ↵
    1. Shibuya K,
    2. Okada M,
    3. Suzuki S,
    4. Seino M,
    5. Seino S,
    6. Takeda H,
    7. Kitanaka C
    : Targeting the facilitative glucose transporter GLUT1 inhibits the self-renewal and tumor-initiating capacity of cancer stem cells. Oncotarget 6(2): 651-661, 2015. PMID: 25528771. DOI: 10.18632/oncotarget.2892
    OpenUrlCrossRefPubMed
  34. ↵
    1. Nukaga S,
    2. Yasuda H,
    3. Tsuchihara K,
    4. Hamamoto J,
    5. Masuzawa K,
    6. Kawada I,
    7. Naoki K,
    8. Matsumoto S,
    9. Mimaki S,
    10. Ikemura S,
    11. Goto K,
    12. Betsuyaku T,
    13. Soejima K
    : Amplification of EGFR wild-type alleles in non-small cell lung cancer cells confers acquired resistance to mutation-selective EGFR tyrosine kinase inhibitors. Cancer Res 77(8): 2078-2089, 2017. PMID: 28202511. DOI: 10.1158/0008-5472.CAN-16-2359
    OpenUrlAbstract/FREE Full Text
  35. ↵
    1. Hirano T,
    2. Yasuda H,
    3. Tani T,
    4. Hamamoto J,
    5. Oashi A,
    6. Ishioka K,
    7. Arai D,
    8. Nukaga S,
    9. Miyawaki M,
    10. Kawada I,
    11. Naoki K,
    12. Costa DB,
    13. Kobayashi SS,
    14. Betsuyaku T,
    15. Soejima K
    : In vitro modeling to determine mutation specificity of EGFR tyrosine kinase inhibitors against clinically relevant EGFR mutants in non-small-cell lung cancer. Oncotarget 6(36): 38789-38803, 2015. PMID: 26515464. DOI: 10.18632/oncotarget.5887
    OpenUrlCrossRefPubMed
  36. ↵
    1. Okamoto K,
    2. Okamoto I,
    3. Hatashita E,
    4. Kuwata K,
    5. Yamaguchi H,
    6. Kita A,
    7. Yamanaka K,
    8. Ono M,
    9. Nakagawa K
    : Overcoming erlotinib resistance in EGFR mutation-positive non-small cell lung cancer cells by targeting survivin. Mol Cancer Ther 11(1): 204-213, 2012. PMID: 22075159. DOI: 10.1158/1535-7163.mct-11-0638
    OpenUrlAbstract/FREE Full Text
    1. Morgillo F,
    2. Woo JK,
    3. Kim ES,
    4. Hong WK,
    5. Lee HY
    : Heterodimerization of insulin-like growth factor receptor/epidermal growth factor receptor and induction of survivin expression counteract the antitumor action of erlotinib. Cancer Res 66(20): 10100-10111, 2006. PMID: 17047074. DOI: 10.1158/0008-5472.can-06-1684
    OpenUrlAbstract/FREE Full Text
    1. Okamoto K,
    2. Okamoto I,
    3. Okamoto W,
    4. Tanaka K,
    5. Takezawa K,
    6. Kuwata K,
    7. Yamaguchi H,
    8. Nishio K,
    9. Nakagawa K
    : Role of survivin in EGFR inhibitor-induced apoptosis in non-small cell lung cancers positive for EGFR mutations. Cancer Res 70(24): 10402-10410, 2010. PMID: 21159653. DOI: 10.1158/0008-5472.CAN-10-2438
    OpenUrlAbstract/FREE Full Text
  39. ↵
    1. Dai CH,
    2. Shu Y,
    3. Chen P,
    4. Wu JN,
    5. Zhu LH,
    6. Yuan RX,
    7. Long WG,
    8. Zhu YM,
    9. Li J
    : YM155 sensitizes non-small cell lung cancer cells to EGFR-tyrosine kinase inhibitors through the mechanism of autophagy induction. Biochim Biophys Acta Mol Basis Dis 1864(12): 3786-3798, 2018. PMID: 30315932. DOI: 10.1016/j.bbadis.2018.10.015
    OpenUrlCrossRef
  40. ↵
    1. Nakahara T,
    2. Kita A,
    3. Yamanaka K,
    4. Mori M,
    5. Amino N,
    6. Takeuchi M,
    7. Tominaga F,
    8. Hatakeyama S,
    9. Kinoyama I,
    10. Matsuhisa A,
    11. Kudoh M,
    12. Sasamata M
    : YM155, a novel small-molecule survivin suppressant, induces regression of established human hormone-refractory prostate tumor xenografts. Cancer Res 67(17): 8014-8021, 2007. PMID: 17804712. DOI: 10.1158/0008-5472.CAN-07-1343
    OpenUrlAbstract/FREE Full Text
  41. ↵
    1. Ryan BM,
    2. O'Donovan N,
    3. Duffy MJ
    : Survivin: a new target for anti-cancer therapy. Cancer Treat Rev 35(7): 553-562, 2009. PMID: 19559538. DOI: 10.1016/j.ctrv.2009.05.003
    OpenUrlCrossRefPubMed
  42. ↵
    1. Yamaoka T,
    2. Ohba M,
    3. Ohmori T
    : Molecular-targeted therapies for epidermal growth factor receptor and its resistance mechanisms. Int J Mol Sci 18(11), 2017. PMID: 29140271. DOI: 10.3390/ijms18112420
  43. ↵
    1. Dai B,
    2. Yan S,
    3. Lara-Guerra H,
    4. Kawashima H,
    5. Sakai R,
    6. Jayachandran G,
    7. Majidi M,
    8. Mehran R,
    9. Wang J,
    10. Bekele BN,
    11. Baladandayuthapani V,
    12. Yoo SY,
    13. Wang Y,
    14. Ying J,
    15. Meng F,
    16. Ji L,
    17. Roth JA
    : Exogenous restoration of TUSC2 expression induces responsiveness to erlotinib in wildtype epidermal growth factor receptor (EGFR) lung cancer cells through context specific pathways resulting in enhanced therapeutic efficacy. PLoS One 10(6): e0123967, 2015. PMID: 26053020. DOI: 10.1371/journal.pone.0123967
    OpenUrlPubMed
  44. ↵
    1. Raimbourg J,
    2. Joalland MP,
    3. Cabart M,
    4. de Plater L,
    5. Bouquet F,
    6. Savina A,
    7. Decaudin D,
    8. Bennouna J,
    9. Vallette FM,
    10. Lalier L
    : Sensitization of EGFR wild-type non-small cell lung cancer cells to egfr-tyrosine kinase inhibitor erlotinib. Mol Cancer Ther 16(8): 1634-1644, 2017. PMID: 28522592. DOI: 10.1158/1535-7163.MCT-17-0075
    OpenUrlAbstract/FREE Full Text
  45. ↵
    1. Minari R,
    2. Bordi P,
    3. Tiseo M
    : Third-generation epidermal growth factor receptor-tyrosine kinase inhibitors in T790M-positive non-small cell lung cancer: review on emerged mechanisms of resistance. Transl Lung Cancer Res 5(6): 695-708, 2016. PMID: 28149764. DOI: 10.21037/tlcr.2016.12.02
    OpenUrlCrossRefPubMed
  46. ↵
    1. Tang ZH,
    2. Lu JJ
    : Osimertinib resistance in non-small cell lung cancer: Mechanisms and therapeutic strategies. Cancer Lett 420: 242-246, 2018. PMID: 29425688. DOI: 10.1016/j.canlet. 2018.02.004
    OpenUrlCrossRefPubMed
  47. ↵
    1. Le X,
    2. Puri S,
    3. Negrao MV,
    4. Nilsson MB,
    5. Robichaux J,
    6. Boyle T,
    7. Hicks JK,
    8. Lovinger KL,
    9. Roarty E,
    10. Rinsurongkawong W,
    11. Tang M,
    12. Sun H,
    13. Elamin Y,
    14. Lacerda LC,
    15. Lewis J,
    16. Roth JA,
    17. Swisher SG,
    18. Lee JJ,
    19. William WN Jr..,
    20. Glisson BS,
    21. Zhang J,
    22. Papadimitrakopoulou VA,
    23. Gray JE,
    24. Heymach JV
    : Landscape of EGFR-dependent and -independent resistance mechanisms to osimertinib and continuation therapy beyond progression in EGFR-mutant NSCLC. Clin Cancer Res 24(24): 6195-6203, 2018. PMID: 30228210. DOI: 10.1158/1078-0432.CCR-18-1542
    OpenUrlAbstract/FREE Full Text
    1. Taniguchi H,
    2. Yamada T,
    3. Wang R,
    4. Tanimura K,
    5. Adachi Y,
    6. Nishiyama A,
    7. Tanimoto A,
    8. Takeuchi S,
    9. Araujo LH,
    10. Boroni M,
    11. Yoshimura A,
    12. Shiotsu S,
    13. Matsumoto I,
    14. Watanabe S,
    15. Kikuchi T,
    16. Miura S,
    17. Tanaka H,
    18. Kitazaki T,
    19. Yamaguchi H,
    20. Mukae H,
    21. Uchino J,
    22. Uehara H,
    23. Takayama K,
    24. Yano S
    : AXL confers intrinsic resistance to osimertinib and advances the emergence of tolerant cells. Nat Commun 10(1): 259, 2019. PMID: 30651547. DOI: 10.1038/s41467-018-08074-0
    OpenUrlCrossRefPubMed
    1. Namba K,
    2. Shien K,
    3. Takahashi Y,
    4. Torigoe H,
    5. Sato H,
    6. Yoshioka T,
    7. Takeda T,
    8. Kurihara E,
    9. Ogoshi Y,
    10. Yamamoto H,
    11. Soh J,
    12. Tomida S,
    13. Toyooka S
    : Activation of AXL as a preclinical acquired resistance mechanism against osimertinib treatment in EGFR-mutant non-small cell lung cancer cells. Mol Cancer Res 17(2): 499-507, 2019. PMID: 30463991. DOI: 10.1158/1541-7786.MCR-18-0628
    OpenUrlAbstract/FREE Full Text
  50. ↵
    1. Romaniello D,
    2. Mazzeo L,
    3. Mancini M,
    4. Marrocco I,
    5. Noronha A,
    6. Kreitman M,
    7. Srivastava S,
    8. Ghosh S,
    9. Lindzen M,
    10. Salame TM,
    11. Onn A,
    12. Bar J,
    13. Yarden Y
    : A Combination of approved antibodies overcomes resistance of lung cancer to osimertinib by blocking bypass pathways. Clin Cancer Res 24(22): 5610-5621, 2018. PMID: 29967248. DOI: 10.1158/1078-0432.CCR-18-0450
    OpenUrlAbstract/FREE Full Text
  51. ↵
    1. Zheng H,
    2. Yang L,
    3. Kang Y,
    4. Chen M,
    5. Lin S,
    6. Xiang Y,
    7. Li C,
    8. Dai X,
    9. Huang X,
    10. Liang G,
    11. Zhao C
    : Alantolactone sensitizes human pancreatic cancer cells to EGFR inhibitors through the inhibition of STAT3 signaling. Mol Carcinog 58(4): 565-576, 2019. PMID: 30520143. DOI: 10.1002/mc.22951
    OpenUrlPubMed
    1. Du J,
    2. He Y,
    3. Wu W,
    4. Li P,
    5. Chen Y,
    6. Hu Z,
    7. Han Y
    : Targeting EphA2 with miR-124 mediates Erlotinib resistance in K-RAS mutated pancreatic cancer. J Pharm Pharmacol 71(2): 196-205, 2019. PMID: 30604411. DOI: 10.1111/jphp.12941
    OpenUrlPubMed
    1. Halfdanarson TR,
    2. Foster NR,
    3. Kim GP,
    4. Meyers JP,
    5. Smyrk TC,
    6. McCullough AE,
    7. Ames MM,
    8. Jaffe JP,
    9. Alberts SR
    : A phase II randomized trial of panitumumab, erlotinib, and gemcitabine versus erlotinib and gemcitabine in patients with untreated, metastatic pancreatic adenocarcinoma: North Central Cancer Treatment Group Trial N064B (Alliance). Oncologist, 2019. PMID: 30679315. DOI: 10.1634/theoncologist.2018-0878
  54. ↵
    1. Veschi S,
    2. De Lellis L,
    3. Florio R,
    4. Lanuti P,
    5. Massucci A,
    6. Tinari N,
    7. De Tursi M,
    8. di Sebastiano P,
    9. Marchisio M,
    10. Natoli C,
    11. Cama A
    : Effects of repurposed drug candidates nitroxoline and nelfinavir as single agents or in combination with erlotinib in pancreatic cancer cells. J Exp Clin Cancer Res 37(1): 236, 2018. PMID: 30241558. DOI: 10.1186/s13046-018-0904-2
    OpenUrlCrossRefPubMed
  55. ↵
    1. Mobahat M,
    2. Narendran A,
    3. Riabowol K
    : Survivin as a preferential target for cancer therapy. Int J Mol Sci 15(2): 2494-2516, 2014. PMID: 24531137. DOI: 10.3390/ijms15022494
    OpenUrlCrossRefPubMed
  56. ↵
    1. Soleimanpour E,
    2. Babaei E
    : Survivin as a potential target for cancer therapy. Asian Pac J Cancer Prev 16(15): 6187-6191, 2015. PMID: 26434815. DOI: 10.7314/apjcp.2015.16.15.6187
    OpenUrlPubMed
  57. ↵
    1. Wang S,
    2. Xu Y,
    3. Chan HF,
    4. Kim HW,
    5. Wang Y,
    6. Leong KW,
    7. Chen M
    : Nanoparticle-mediated inhibition of survivin to overcome drug resistance in cancer therapy. J Control Release 240: 454-464, 2016. PMID: 27091696. DOI: 10.1016/j.jconrel. 2016.04.018
    OpenUrlPubMed
  58. ↵
    1. Giaccone G,
    2. Zatloukal P,
    3. Roubec J,
    4. Floor K,
    5. Musil J,
    6. Kuta M,
    7. van Klaveren RJ,
    8. Chaudhary S,
    9. Gunther A,
    10. Shamsili S
    : Multicenter phase II trial of YM155, a small-molecule suppressor of survivin, in patients with advanced, refractory, non-small-cell lung cancer. J Clin Oncol 27(27): 4481-4486, 2009. PMID: 19687333. DOI: 10.1200/jco.2008.21.1862
    OpenUrlAbstract/FREE Full Text
  59. ↵
    1. Clemens MR,
    2. Gladkov OA,
    3. Gartner E,
    4. Vladimirov V,
    5. Crown J,
    6. Steinberg J,
    7. Jie F,
    8. Keating A
    : Phase II, multicenter, open-label, randomized study of YM155 plus docetaxel as first-line treatment in patients with HER2-negative metastatic breast cancer. Breast Cancer Res Treat 149(1): 171-179, 2015. PMID: 25547219. DOI: 10.1007/s10549-014-3238-6
    OpenUrlCrossRefPubMed
    1. Kelly RJ,
    2. Thomas A,
    3. Rajan A,
    4. Chun G,
    5. Lopez-Chavez A,
    6. Szabo E,
    7. Spencer S,
    8. Carter CA,
    9. Guha U,
    10. Khozin S,
    11. Poondru S,
    12. Van Sant C,
    13. Keating A,
    14. Steinberg SM,
    15. Figg W,
    16. Giaccone G
    : A phase I/II study of sepantronium bromide (YM155, survivin suppressor) with paclitaxel and carboplatin in patients with advanced non-small-cell lung cancer. Ann Oncol 24(10): 2601-2606, 2013. PMID: 23857959. DOI: 10.1093/annonc/mdt249
    OpenUrlCrossRefPubMed
  61. ↵
    1. Kudchadkar R,
    2. Ernst S,
    3. Chmielowski B,
    4. Redman BG,
    5. Steinberg J,
    6. Keating A,
    7. Jie F,
    8. Chen C,
    9. Gonzalez R,
    10. Weber J
    : A phase 2, multicenter, open-label study of sepantronium bromide (YM155) plus docetaxel in patients with stage III (unresectable) or stage IV melanoma. Cancer Med 4(5): 643-650, 2015. PMID: 25533314. DOI: 10.1002/cam4.363
    OpenUrlPubMed
  62. ↵
    1. Wiechno P,
    2. Somer BG,
    3. Mellado B,
    4. Chlosta PL,
    5. Cervera Grau JM,
    6. Castellano D,
    7. Reuter C,
    8. Stockle M,
    9. Kamradt J,
    10. Pikiel J,
    11. Duran I,
    12. Wedel S,
    13. Callies S,
    14. Andre V,
    15. Hurt K,
    16. Brown J,
    17. Lahn M,
    18. Heinrich B
    : A randomised phase 2 study combining LY2181308 sodium (survivin antisense oligonucleotide) with first-line docetaxel/prednisone in patients with castration-resistant prostate cancer. Eur Urol 65(3): 516-520, 2014. PMID: 24246407. DOI: 10.1016/j.eururo.2013.10.039
    OpenUrlCrossRefPubMed
  63. ↵
    1. Talbot DC,
    2. Ranson M,
    3. Davies J,
    4. Lahn M,
    5. Callies S,
    6. Andre V,
    7. Kadam S,
    8. Burgess M,
    9. Slapak C,
    10. Olsen AL,
    11. McHugh PJ,
    12. de Bono JS,
    13. Matthews J,
    14. Saleem A,
    15. Price P
    : Tumor survivin is downregulated by the antisense oligonucleotide LY2181308: a proof-of-concept, first-in-human dose study. Clin Cancer Res 16(24): 6150-6158, 2010. PMID: 21041181. DOI: 10.1158/1078-0432.CCR-10-1932
    OpenUrlAbstract/FREE Full Text
  64. ↵
    1. Navari RM,
    2. Qin R,
    3. Ruddy KJ,
    4. Liu H,
    5. Powell SF,
    6. Bajaj M,
    7. Dietrich L,
    8. Biggs D,
    9. Lafky JM,
    10. Loprinzi CL
    : Olanzapine for the prevention of chemotherapy-induced nausea and vomiting. N Engl J Med 375(2): 134-142, 2016. PMID: 27410922. DOI: 10.1056/NEJMoa1515725
    OpenUrlCrossRefPubMed
  65. ↵
    1. Nelson JC,
    2. Weiller E,
    3. Zhang P,
    4. Weiss C,
    5. Hobart M
    : Efficacy of adjunctive brexpiprazole on the core symptoms of major depressive disorder: A post hoc analysis of two pooled clinical studies. J Affect Disord 227: 103-108, 2018. PMID: 29055257. DOI: 10.1016/j.jad.2017.09.054
    OpenUrlPubMed
  66. ↵
    1. Thase ME,
    2. Youakim JM,
    3. Skuban A,
    4. Hobart M,
    5. Zhang P,
    6. McQuade RD,
    7. Nyilas M,
    8. Carson WH,
    9. Sanchez R,
    10. Eriksson H
    : Adjunctive brexpiprazole 1 and 3 mg for patients with major depressive disorder following inadequate response to antidepressants: a phase 3, randomized, double-blind study. J Clin Psychiatry 76(9): 1232-1240, 2015. PMID: 26301771. DOI: 10.4088/JCP.14m09689
    OpenUrlPubMed
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Brexpiprazole Reduces Survivin and Reverses EGFR Tyrosine Kinase Inhibitor Resistance in Lung and Pancreatic Cancer
TOMOMI SANOMACHI, SHUHEI SUZUKI, KEITA TOGASHI, SHIZUKA SEINO, TAKASHI YOSHIOKA, CHIFUMI KITANAKA, MASASHI OKADA, MASAHIRO YAMAMOTO
Anticancer Research Sep 2019, 39 (9) 4817-4828; DOI: 10.21873/anticanres.13667
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