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EGFR and c-MET Cooperate to Enhance Resistance to PARP Inhibitors in Hepatocellular Carcinoma

journal contribution
submitted on 2024-05-28, 10:26 and posted on 2024-05-28, 10:27 authored by 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

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.

Significance:

Regulation of PARP by the c-MET and EGFR heterodimer suggests a potentially effective combination therapy to sensitize HCC to PARPi.


Other Information

Published in: Cancer Research
License: https://creativecommons.org/licenses/by/4.0/
See article on publisher's website: https://doi.org/10.1158/0008-5472.can-18-1273

Funding

Open Access funding provided by the Qatar National Library.

History

Language

  • English

Publisher

American Association for Cancer Research

Publication Year

  • 2019

License statement

This Item is licensed under the Creative Commons Attribution 4.0 International License

Institution affiliated with

  • Hamad Bin Khalifa University
  • College of Science and Engineering - HBKU
  • Qatar Biomedical Research Institute - HBKU
  • Cancer Research Center - QBRI

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