Epidermal growth factor receptor in tumor angiogenesis

The present study involves design and synthesis of five series of 6-bromo-2-(pyridin-3-yl)-4-substituted quinazolines 9a-l, 11a-e, 13a-c, 14a-f and 15a-e. Candidates 9a-l and 11a-e were evaluated for their EGFR and HER2 inhibitory activity compared to Lapatinib. Compounds 9b, 9d, 9f, 11b and 11c were further screened for their in vitro cytotoxicity against two human breast cancer cell lines: AU-565 and MDA-MB-231 in addition to normal breast cell line MCF10A. Compound 9d revealed a remarkable cytotoxic efficacy against AU-565 cell line (IC₅₀ = 1.54 µM) relative to Lapatinib (IC₅₀ = 0.48 µM), whereas compounds 9d and 11c showed a superior cytotoxicity towards MDA-MB-231 (IC₅₀ = 2.67 and 1.75 µM, respectively) in comparison to Lapatinib (IC₅₀ = 9.29 µM). Moreover, compounds 13a-c, 13a-c, 14a-f and 15a-e were tested for their VEGFR-2 inhibitory activity compared to Sorafenib. Compounds 13a, 14c and 14e exhibited remarkable inhibition (IC₅₀ = 79.80, 50.22 and 78.02 nM, respectively) relative to Sorafenib (IC₅₀ = 51.87 nM). In vitro cytotoxicity of these compounds against HepG2, HCT-116 and normal cell (WISH) revealed a superior cytotoxicity against HepG2, HCT-116 especially 13a (IC₅₀ = 17.51 and 5.56 µM, respectively) and 14c (IC₅₀ = 10.40 and 3.37 µM, respectively) compared to Sorafenib (IC₅₀ = 19.33 and 6.82 µM, respectively). Compounds 9d, 11c and 14c were subjected to cell cycle analysis and apoptotic assay. Molecular docking and ADME prediction studies were fulfilled to illustrate the interaction of the potent derivatives with the hot spots of the active site of EGFR, HER2 and VEGFR-2 along with prediction of their pharmacokinetic and physicochemical properties.

Pancreatic cancer (PCa) is one of the leading causes of morbidity worldwide, and theranostic approaches are ventured. The vast stroma surrounding PCa cells has been proven to play a pivotal role in tumor growth and invasion, sequestering chemotherapeutic drugs and reducing their delivery to tumor cells. By exploiting the enhanced permeability and retention (EPR) effect, nanotechnology has risen to the top of medical imaging and therapeutic modalities. The EPR effect is now considered a promising approach for delivering drug-loaded nanostructures to tumors. However, its application is limited due to a disordered vascular network and blocked or embolized blood vessels. Desmoplastic tumors have a dense stroma, so the permeability of the particles into the tumor is low, and these tumors are resistant to nanoparticle-based chemotherapy. There are several strategies for improving the EPR effect by modulating tumor blood vessels, angiogenesis, vascular structure, blood flow, and other factors affecting EPR. Furthermore, by modulating tumor vessels using nanostructures (i.e., nanoparticles (NPs), liposomes, micelles, polymers, nano-biomimetics, etc.) for drug delivery, the EPR effect can be significantly improved. This review will focus on the possible uses of nanostructures to deliver therapeutic drugs for PCa imaging and treatment via the EPR-mediated effect.

Tumor growth is driven by abundant signaling pathways. Tumors can circumvent one signaling blockade and generate resistance by utilizing the redundancy in growth signaling. Therefore, combining inhibitors of more than one pathway may be a rational strategy against tumor resistance. Vascular endothelial growth factor (VEGF) and EGFR pathways are interrelated. Activation of EGFR is known to induce the secretion of multiple paracrine angiogenic growth factors in cancer cells, such as VEGF, transforming growth factor alpha, basic fibroblast growth factor, and interleukin-8. Increased levels of VEGF lead to neovascularization within the tumor and acquired resistance to EGFR inhibitors. ZD6474 (vandetanib) is a small-molecule inhibitor of VEGF receptor-2 (VEGFR-2), EGFR, and RET tyrosine kinase activity. A previous study showed that ZD6474 overcomes acquired resistance to anti-EGFR therapy as monotherapy. Another study found that the combination of ZD6474 with EGFR inhibitors has synergistic antitumor activity in a series of human cancers. Collectively, double blockade of EGFR and VEGFR-2 signaling using ZD6474 presents potential and is worth further evaluation in clinical settings.

Although mutations of genes are crucial events in tumorigenesis and development, the association between gene mutations and lung cancer metastasis is still largely unknown. The goal of this study is to identify driver and novel genes associated with non-small cell lung cancer (NSCLC) metastasis. Candidate genes were identified using a novel comprehensive analysis, which was based on bioinformatics technology and meta-analysis. Firstly, EGFR, KRAS, ALK, TP53, BRAF and PIK3CA were identified as candidate driver genes. Further meta-analysis identified that EGFR (Pooled OR 1.33, 95% CI 1.19, 1.50; P < .001) and ALK (Pooled OR 1.52, 95% CI 1.22, 1.89; P < .001) mutations were associated with distant metastasis of NSCLC. Besides, ALK (Pooled OR 2.40, 95% CI 1.71, 3.38; P < .001) mutation was associated with lymph node metastasis of NSCLC. In addition, thirteen novel gene mutations were identified to be correlated with NSCLC metastasis, including SMARCA1, GGCX, KIF24, LRRK1, LILRA4, OR2T10, EDNRB, NR1H4, ARID4A, PRKCI, PABPC5, ACAN and TLN1. Furthermore, elevated mRNA expression level of SMARCA1 and EDNRB was associated with poor overall survival in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), respectively. Additionally, pathway and protein-protein interactions network analyses found the two genes were correlated with epithelial-mesenchymal transition process. In conclusion, mutations of EGFR and ALK were significantly correlated with NSCLC metastasis. In addition, thirteen novel genes were identified to be associated with NSCLC metastasis, especially SMARCA1 in LUAD and EDNRB in LUSC.

In this paper, based on molecular hybridization, a series of [1,2,3]triazolo[4,5-d]pyrimidine derivatives containing hydrazine was synthesized and their antiproliferative activities against 5 cancer cell lines (MGC-803, PC3, PC9, EC9706 and SMMC-7721) were evaluated. We found that most of them exhibited obvious growth inhibition effects on these tested cancer cells, especially compound 34 on PC3 cells (IC₅₀ = 26.25 ± 0.28 nM). Meanwhile, compound 34 displayed best selectivity on PC3, compared with the other cancer cell lines, as well as excellent selectivity towards normal cell lines (Het-1A, L02 and GES-1). Further investigations demonstrated that 34 could significantly inhibit PC3 cells’ colony formation, increase cellular ROS content, suppress EGFR expression and induce apoptosis. Our findings indicate that 34 may serve as a novel lead compound for the discovery of more triazolopyrimidine derivatives with improved anticancer potency and selectivity.