Abstract 4074: Reversing acquired PARPi resistance of TNBC through combined inhibition of cMet and EGFR

Abstract

Abstract Front line therapeutic failure happened to half of triple-negative breast cancer (TNBC) patients represent the effective treatment strategies for these patients are urgently needed. Poly (ADP-ribose) polymerase (PARP) is currently the most promising drug target for BRCA-mutated TNBC, and PARP inhibitors (PARPi), olaparib and talazoparib, were recently approved for the treatment of metastatic breast cancer (including TNBC) in patients with germline BRCA1/2 mutations. Despite impressive response rates of ~60%, the prolongation in median progression-free survival with a PARPi is modest, suggesting the emergence of resistance. Several studies have reported that receptor tyrosine kinases (RTKs), such as c-MET (also known as hepatocyte growth factor receptor), are involved in resistance to various anti-neoplastic agents, including PARPi. However, the mechanism by which c-MET contributes to acquired resistance to PARPi in TNBC is not fully understood. In this study, we analyzed acquired PARPi resistant TNBC cells and found c-Met is hyperactivated in these cells with PARPi treatment. We further treated these cells with talazoparib and crizotinib (a multi-kinase inhibitor that inhibits c-MET) and found synergistic inhibition effects of cell proliferation. Unexpectedly, limited effects of talazoparib sensitivity showed while depleting c-MET in PARPi-resistant cells. Interestingly, we found epidermal growth factor receptor (EGFR) is also hyperactivated and interaction of EGFR/c-Met in these cells. Notably, combination of c-MET and EGFR inhibitors increased sensitivity to talazoparib in TNBC cells with acquired resistance to PARPi. Combining EGFR and PARP inhibitors also resulted in greater inhibition of proliferation in c-MET-depleted TNBC cells. Collectively, our findings suggested a potential combination therapy of inhibiting c-MET and EGFR to overcome acquired PARPi resistance in TNBC. Citation Format: Yu Yi Chu, Clinton Yam, Mei-Kuang Chen, Li-Chuan Chan, Lei Nie, Mien-Chie Hung. Reversing acquired PARPi resistance of TNBC through combined inhibition of cMet and EGFR [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4074.