EGFR and c-MET Cooperate to Enhance Resistance to PARP Inhibitors in Hepatocellular Carcinoma
<p dir="ltr">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 d...
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| مؤلفون آخرون: | , , , , , , , , , , |
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2019
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| _version_ | 1864513513573056512 |
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| author | Qiongzhu Dong (5156150) |
| author2 | Yi Du (634812) Hui Li (32376) Chunxiao Liu (436462) Yongkun Wei (9694532) Mei-Kuang Chen (14917347) Xixi Zhao (4251673) Yu-Yi Chu (636524) Yufan Qiu (8734875) Lunxiu Qin (624841) Hirohito Yamaguchi (14884460) Mien-Chie Hung (102628) |
| author2_role | author author author author author author author author author author author |
| author_facet | Qiongzhu Dong (5156150) Yi Du (634812) Hui Li (32376) Chunxiao Liu (436462) Yongkun Wei (9694532) Mei-Kuang Chen (14917347) Xixi Zhao (4251673) Yu-Yi Chu (636524) Yufan Qiu (8734875) Lunxiu Qin (624841) Hirohito Yamaguchi (14884460) Mien-Chie Hung (102628) |
| author_role | author |
| dc.creator.none.fl_str_mv | Qiongzhu Dong (5156150) Yi Du (634812) Hui Li (32376) Chunxiao Liu (436462) Yongkun Wei (9694532) Mei-Kuang Chen (14917347) Xixi Zhao (4251673) Yu-Yi Chu (636524) Yufan Qiu (8734875) Lunxiu Qin (624841) Hirohito Yamaguchi (14884460) Mien-Chie Hung (102628) |
| dc.date.none.fl_str_mv | 2019-02-15T15:00:00Z |
| dc.identifier.none.fl_str_mv | 10.57945/manara.hbku.25912042.v1 |
| dc.relation.none.fl_str_mv | https://figshare.com/articles/journal_contribution/EGFR_and_c-MET_Cooperate_to_Enhance_Resistance_to_PARP_Inhibitors_in_Hepatocellular_Carcinoma/25912042 |
| dc.rights.none.fl_str_mv | CC BY 4.0 info:eu-repo/semantics/openAccess |
| dc.subject.none.fl_str_mv | Biomedical and clinical sciences Oncology and carcinogenesis PARP1 inhibitors (PARPi) Hepatocellular carcinoma (HCC) Therapeutic efficacy Biomarkers PARPi resistance EGFR MET |
| dc.title.none.fl_str_mv | EGFR and c-MET Cooperate to Enhance Resistance to PARP Inhibitors in Hepatocellular Carcinoma |
| dc.type.none.fl_str_mv | Text Journal contribution info:eu-repo/semantics/publishedVersion text contribution to journal |
| description | <p dir="ltr">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.</p><p dir="ltr">Significance:</p><p dir="ltr">Regulation of PARP by the c-MET and EGFR heterodimer suggests a potentially effective combination therapy to sensitize HCC to PARPi.</p><p><br></p><h2>Other Information</h2><p dir="ltr">Published in: Cancer Research <br>License: <a href="https://creativecommons.org/licenses/by/4.0/" target="_blank">https://creativecommons.org/licenses/by/4.0/</a><br>See article on publisher's website: <a href="https://doi.org/10.1158/0008-5472.can-18-1273" target="_blank">https://doi.org/10.1158/0008-5472.can-18-1273</a></p> |
| eu_rights_str_mv | openAccess |
| id | Manara2_41ca3d20741b1364b6f2af167299de59 |
| identifier_str_mv | 10.57945/manara.hbku.25912042.v1 |
| network_acronym_str | Manara2 |
| network_name_str | Manara2 |
| oai_identifier_str | oai:figshare.com:article/25912042 |
| publishDate | 2019 |
| repository.mail.fl_str_mv | |
| repository.name.fl_str_mv | |
| repository_id_str | |
| rights_invalid_str_mv | CC BY 4.0 |
| spelling | EGFR and c-MET Cooperate to Enhance Resistance to PARP Inhibitors in Hepatocellular CarcinomaQiongzhu Dong (5156150)Yi Du (634812)Hui Li (32376)Chunxiao Liu (436462)Yongkun Wei (9694532)Mei-Kuang Chen (14917347)Xixi Zhao (4251673)Yu-Yi Chu (636524)Yufan Qiu (8734875)Lunxiu Qin (624841)Hirohito Yamaguchi (14884460)Mien-Chie Hung (102628)Biomedical and clinical sciencesOncology and carcinogenesisPARP1 inhibitors (PARPi)Hepatocellular carcinoma (HCC)Therapeutic efficacyBiomarkersPARPi resistanceEGFRMET<p dir="ltr">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.</p><p dir="ltr">Significance:</p><p dir="ltr">Regulation of PARP by the c-MET and EGFR heterodimer suggests a potentially effective combination therapy to sensitize HCC to PARPi.</p><p><br></p><h2>Other Information</h2><p dir="ltr">Published in: Cancer Research <br>License: <a href="https://creativecommons.org/licenses/by/4.0/" target="_blank">https://creativecommons.org/licenses/by/4.0/</a><br>See article on publisher's website: <a href="https://doi.org/10.1158/0008-5472.can-18-1273" target="_blank">https://doi.org/10.1158/0008-5472.can-18-1273</a></p>2019-02-15T15:00:00ZTextJournal contributioninfo:eu-repo/semantics/publishedVersiontextcontribution to journal10.57945/manara.hbku.25912042.v1https://figshare.com/articles/journal_contribution/EGFR_and_c-MET_Cooperate_to_Enhance_Resistance_to_PARP_Inhibitors_in_Hepatocellular_Carcinoma/25912042CC BY 4.0info:eu-repo/semantics/openAccessoai:figshare.com:article/259120422019-02-15T15:00:00Z |
| spellingShingle | EGFR and c-MET Cooperate to Enhance Resistance to PARP Inhibitors in Hepatocellular Carcinoma Qiongzhu Dong (5156150) Biomedical and clinical sciences Oncology and carcinogenesis PARP1 inhibitors (PARPi) Hepatocellular carcinoma (HCC) Therapeutic efficacy Biomarkers PARPi resistance EGFR MET |
| status_str | publishedVersion |
| title | EGFR and c-MET Cooperate to Enhance Resistance to PARP Inhibitors in Hepatocellular Carcinoma |
| title_full | EGFR and c-MET Cooperate to Enhance Resistance to PARP Inhibitors in Hepatocellular Carcinoma |
| title_fullStr | EGFR and c-MET Cooperate to Enhance Resistance to PARP Inhibitors in Hepatocellular Carcinoma |
| title_full_unstemmed | EGFR and c-MET Cooperate to Enhance Resistance to PARP Inhibitors in Hepatocellular Carcinoma |
| title_short | EGFR and c-MET Cooperate to Enhance Resistance to PARP Inhibitors in Hepatocellular Carcinoma |
| title_sort | EGFR and c-MET Cooperate to Enhance Resistance to PARP Inhibitors in Hepatocellular Carcinoma |
| topic | Biomedical and clinical sciences Oncology and carcinogenesis PARP1 inhibitors (PARPi) Hepatocellular carcinoma (HCC) Therapeutic efficacy Biomarkers PARPi resistance EGFR MET |