Poly (ADP-ribose) polymerase-1 (PARP-1) inhibitors are currently used in the clinic for the treatment of ovarian and breast cancers. However, the therapeutic efficacy of PARP inhibitor (PARPi) in the clinical trial for hepatocellular carcinoma (HCC) has been disappointing. To ensure therapeutic efficacy of PARPi against HCC, a disease often diagnosed at intermediate to advanced stages with no effective treatment options, it is critical to identify not only biomarkers to predict PARPi resistance but also rational combination treatments to overcome this. Here, we demonstrate that EGFR forms a heterodimer with c-MET, and the complex interacts with and phosphorylates Y907 PARP1 in the nucleus contributing to PARPi resistance. Inhibition of both EGFR and c-MET sensitizes HCC cells to PARPi. Combination of EGFRi, METi and PARPi significantly inhibited tumor growth in HCC animal model. Both EGFR and c-MET are known to be overexpressed in HCC. The current report provides a rationale to explain why PARPi does not work in clinical trials for HCC and also suggests an effective combination treatment consisting of EGFR, c-Met, and PARP inhibitors for HCC.
Note: This abstract was not presented at the meeting.
Citation Format: Qiongzhu Dong, Yi Du, Xixi Zhao, Hui Li, Chunxiao Liu, Yongkun Wei, Mien-chie Hung. EGFR and c-MET cooperate to enhance PARP inhibitor resistance in hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-258.