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

doi:10.1158/0008-5472.CAN-18-1273

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 journal › Article › peer-review

47 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 language	English (US)
Pages (from-to)	819-829
Number of pages	11
Journal	Cancer Research
Volume	79
Issue number	4
DOIs	https://doi.org/10.1158/0008-5472.CAN-18-1273
State	Published - Feb 15 2019

ASJC Scopus subject areas

Oncology
Cancer Research

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Functional Genomics Core
Advanced Technology Genomics Core
Cytogenetics and Cell Authentication Core

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10.1158/0008-5472.CAN-18-1273

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title = "EGFR and c-Met cooperate to enhance resistance to PARP inhibitors in hepatocellular carcinoma",

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.",

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

note = "Funding Information: This study was supported by the following: NIH (CCSG CA016672, R01 CA211615, and U01 CA201777); Cancer Prevention and Research Institutes of Texas (RP160710); The University of Texas MD Anderson-China Medical University and Hospital Sister Institution Fund (to M-C. Hung); Ministry of Health and Welfare, China Medical University Hospital Cancer Research Center of Excellence (MOHW107-TDU-B-212-114024 and MOHW107-TDU-B-212-112015); Center for Biological Pathways; and the National Key Research and Development Program of China (2017YFC1308604). Publisher Copyright: {\textcopyright} 2018 American Association for Cancer Research.",

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doi = "10.1158/0008-5472.CAN-18-1273",

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T1 - EGFR and c-Met cooperate to enhance resistance to PARP inhibitors in hepatocellular carcinoma

AU - Dong, Qiongzhu

AU - Du, Yi

AU - Li, Hui

AU - Liu, Chunxiao

AU - Wei, Yongkun

AU - Chen, Mei Kuang

AU - Zhao, Xixi

AU - Chu, Yu Yi

AU - Qiu, Yufan

AU - Qin, Lunxiu

AU - Yamaguchi, Hirohito

AU - Hung, Mien Chie

N1 - Funding Information: This study was supported by the following: NIH (CCSG CA016672, R01 CA211615, and U01 CA201777); Cancer Prevention and Research Institutes of Texas (RP160710); The University of Texas MD Anderson-China Medical University and Hospital Sister Institution Fund (to M-C. Hung); Ministry of Health and Welfare, China Medical University Hospital Cancer Research Center of Excellence (MOHW107-TDU-B-212-114024 and MOHW107-TDU-B-212-112015); Center for Biological Pathways; and the National Key Research and Development Program of China (2017YFC1308604). Publisher Copyright: © 2018 American Association for Cancer Research.

PY - 2019/2/15

Y1 - 2019/2/15

N2 - 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.

AB - 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.

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

Abstract

ASJC Scopus subject areas

MD Anderson CCSG core facilities

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