Blocking c-Met and EGFR reverses acquired resistance of PARP inhibitors in triple-negative breast cancer.

Abstract

The limited treatment options and therapeutic failure due to acquired resistance for patients with triple-negative breast cancer (TNBC) represent a significant challenge. Inhibitors against poly (ADP-ribose) polymerase (PARP), 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 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.

• Authors: Yu-Yi Chu, Clinton Yam, Mei-Kuang Chen, Li-Chuan Chan, Min Xiao, Yong-Kun Wei, Hirohito Yamaguchi, Pei-Chih Lee, Ye Han, Lei Nie, Xian Sun, Stacy L Moulder, Kenneth R Hess, Bin Wang, Jennifer L Hsu, Gabriel N Hortobagyi, Jennifer Litton, Jeffrey T Chang, Mien-Chie Hung
• Journal: American journal of cancer research (Am J Cancer Res) Vol. 10 Issue 2 Pg. 648-661 ( 2020) ISSN: 2156-6976 [Print] United States
• PMID: 32195033 (Publication Type: Journal Article)
• Copyright: AJCR Copyright © 2020.