EGFR and c-Met cooperate to enhance resistance to PARP inhibitors in hepatocellular carcinoma

Qiongzhu Dong, Yi Du, Hui Li, Chunxiao Liu, Yongkun Wei, Mei Kuang Chen, Xixi Zhao, Yu Yi Chu, Yufan Qiu, Lunxiu Qin, Hirohito Yamaguchi, Mien Chie Hung

Research output: Contribution to journalArticle

4 Scopus citations

Abstract

PARP1 inhibitors (PARPi) are currently used in the clinic for the treatment of ovarian and breast cancers, yet their therapeutic efficacy against 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 treatments to overcome this. Here, we report that a heterodimer of EGFR and MET interacts with and phosphorylates Y907 of PARP1 in the nucleus, which contributes to PARPi resistance. Inhibition of both EGFR and MET sensitized HCC cells to PARPi, and both EGFR and MET are known to be overexpressed in HCC. This report provides an explanation for the poor efficacy of PARPi against HCC and suggests combinatorial treatment consisting of EGFR, MET, and PARP inhibitors may be an effective therapeutic strategy in HCC.

Original languageEnglish (US)
Pages (from-to)819-829
Number of pages11
JournalCancer Research
Volume79
Issue number4
DOIs
StatePublished - Feb 15 2019
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Dong, Q., Du, Y., Li, H., Liu, C., Wei, Y., Chen, M. K., Zhao, X., Chu, Y. Y., Qiu, Y., Qin, L., Yamaguchi, H., & Hung, M. C. (2019). EGFR and c-Met cooperate to enhance resistance to PARP inhibitors in hepatocellular carcinoma. Cancer Research, 79(4), 819-829. https://doi.org/10.1158/0008-5472.CAN-18-1273