PT  - JOURNAL ARTICLE
AU  - KIM, CHORONG
AU  - KIM, DANBEE
AU  - LEE, DA SOL
AU  - LEE, SEONMIN
AU  - YOO, CHANGHOON
AU  - KIM, KYU-PYO
TI  - PARP Inhibitor Sensitizes <em>BRCA</em>-mutant Pancreatic Cancer to Oxaliplatin by Suppressing the CDK1/BRCA1 Axis
AID  - 10.21873/anticanres.16754
DP  - 2023 Dec 01
TA  - Anticancer Research
PG  - 5523--5534
VI  - 43
IP  - 12
4099  - http://ar.iiarjournals.org/content/43/12/5523.short
4100  - http://ar.iiarjournals.org/content/43/12/5523.full
SO  - Anticancer Res2023 Dec 01; 43
AB  - Background/Aim: Currently, olaparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, has been approved as maintenance therapy for patients with germline BRCA mutations and metastatic pancreatic cancer. However, platinum-based chemotherapy, which induces synthetic lethality with PARP inhibitor treatment, is still controversial. Hence, we aimed to examine a platinum-based drug in combination with a PARP inhibitor and generate data regarding the use of a PARP inhibitor in the overall treatment of pancreatic cancer. Materials and Methods: Using the Capan-1 cell line (BRCA2-mutant pancreatic cancer cell line), we evaluated the combinatorial effects of olaparib, a PARP inhibitor, and oxaliplatin by cell viability, combination index, western blotting, immunocytochemistry, flow cytometry, apoptosis assays and in vivo experiments. Results: Capan-1 cells showed high sensitivity to olaparib due to the alteration in PARP activity, which led to cell death through the accumulation of oxaliplatin-induced DNA damage. Beyond DNA damage, oxaliplatin also suppressed the CDK1/BRCA1 signaling axis, which induced defects in homologous recombination repair. Additionally, inhibition of CDK1, a biomarker for oxaliplatin efficacy, induced cell death regardless of the BRCA mutation profile. Conclusion: Oxaliplatin may be used in combination with olaparib in PDAC patients with DNA damage repair mutations. Our findings highlight CDK1 as a potential therapeutic target for pancreatic cancer.