Abstract LB097: MET inhibitor enhances efficacies of gemcitabine and olaparib in pancreatic cancer cells

Mei-Kuang Chen, Yuan Gao, Dihua Yu, M. Hung
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Abstract

Gemcitabine is one of the current first-line chemotherapy agents in pancreatic cancer treatment. However, the response rate of pancreatic cancer patients to gemcitabine treatment is lower than 20%. Among the potential targeted therapies for pancreatic cancer patients, PARP inhibitor (Olaparib) has been approved by the U.S. Food and Drug Administration for maintenance treatment of metastatic pancreatic adenocarcinoma patients with germline BRCA-mutation. Taking advantages of the high oxidative stress in most pancreatic cancer cells, therapeutic agents that enhance the burden of oxidative DNA damages in these cancer cells can be introduced in novel treatment strategies. Because c-MET overexpression positively correlates with poor prognosis in pancreatic cancer, and our previous studies show that oxidative stress induced-nuclear c-MET phosphorylates PARP1 to reduce oxidative DNA damages, we focused on developing novel treatment strategies by combining c-MET inhibitors (crizotinib and tivantinib) with either gemcitabine or olaparib. In this study, we found that gemcitabine induced nuclear accumulation of c-MET, and that tivantinib reduced c-MET mediated PARP1 phosphorylation in both BxPC-3 and L3.6pl pancreatic cancer cell lines. We also found that combination of tivantinib with either gemcitabine or Olaparib induced more DNA damages than the single agent treatments. Further, we demonstrated the synergistic effects of c-MET inhibitors combined with gemcitabine or Olaparib in pancreatic cancer cell lines, suggesting that combining c-MET inhibitor with PARP inhibitor or gemcitabine is a novel and rational therapeutic strategy for pancreatic cancer treatment. Citation Format: Meikuang Chen, Yuan Gao, Dihua Yu, Mien-Chie Hung. MET inhibitor enhances efficacies of gemcitabine and olaparib in pancreatic cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB097.
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LB097: MET抑制剂增强吉西他滨和奥拉帕尼对胰腺癌细胞的作用
吉西他滨是目前治疗胰腺癌的一线化疗药物之一。然而,胰腺癌患者对吉西他滨治疗的应答率低于20%。在胰腺癌患者的潜在靶向治疗中,PARP抑制剂(Olaparib)已被美国食品和药物管理局批准用于转移性胰腺腺癌种系brca突变患者的维持治疗。利用大多数胰腺癌细胞的高氧化应激,可以引入增加这些癌细胞氧化DNA损伤负担的治疗药物,以实现新的治疗策略。由于c-MET过表达与胰腺癌的不良预后正相关,并且我们之前的研究表明氧化应激诱导的核c-MET磷酸化PARP1以减少氧化DNA损伤,因此我们专注于开发新的治疗策略,将c-MET抑制剂(克里唑替尼和tivantinib)与吉西他滨或奥拉帕尼联合使用。在本研究中,我们发现吉西他滨诱导了c-MET的核积累,而在BxPC-3和L3.6pl胰腺癌细胞系中,tivantinib降低了c-MET介导的PARP1磷酸化。我们还发现,与单药治疗相比,tivantinib与吉西他滨或奥拉帕尼联合使用会引起更多的DNA损伤。此外,我们证实了c-MET抑制剂与吉西他滨或奥拉帕尼在胰腺癌细胞系中的协同作用,表明c-MET抑制剂与PARP抑制剂或吉西他滨联合是一种新的、合理的胰腺癌治疗策略。引用格式:陈美匡,高元,余迪华,洪敏智。MET抑制剂增强吉西他滨和奥拉帕尼对胰腺癌细胞的疗效[摘要]。见:美国癌症研究协会2021年年会论文集;2021年4月10日至15日和5月17日至21日。费城(PA): AACR;癌症杂志,2021;81(13 -增刊):摘要nr LB097。
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