Blocking c-Met and EGFR reverses acquired resistance of PARP inhibitors in triple-negative breast cancer.
Yu‐Yi Chu, Clinton Yam, Mei‐Kuang Chen, Li-Chuan Chan, Min Xiao, Yongkun Wei, Hirohito Yamaguchi, Pei‐Chih Lee, Ye Han, Lei Nie, Xian Wen Sun, Stacy L. Moulder, Kenneth R. Hess, Bin Wang, Jennifer L. Hsu, Gabriel N. Hortobágyi, Jennifer K. Litton, Jeffrey T. Chang, Mien‐Chie Hung
Abstract
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 show that hyperactivated c-Met is detected in TNBC cells with acquired resistance to PARPi, and the combination of talazoparib and crizotinib (a multi-kinase inhibitor that inhibits c-MET) synergistically inhibits proliferation in these cells. Unexpectedly, depleting c-MET had limited effect on talazoparib sensitivity in PARPi-resistant cells. Interestingly, we found evidence of epidermal growth factor receptor (EGFR) hyperactivation and interaction of EGFR/c-Met in these cells. Notably, combining EGFR and PARP inhibitors resulted in greater inhibition of proliferation in c-MET-depleted TNBC cells, and combined c-MET and EGFR inhibition increased sensitivity to talazoparib in TNBC cells with acquired resistance to PARPi. Our findings suggest that combined inhibition of c-MET and EGFR could potentially re-sensitize TNBC to the cytotoxic effects of PARPi.