The tumor suppressor protein OPCML potentiates anti-EGFR and anti-HER2 targeted therapy in HER2-positive ovarian and breast cancer.

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Title: The tumor suppressor protein OPCML potentiates anti-EGFR and anti-HER2 targeted therapy in HER2-positive ovarian and breast cancer.
Authors: Zanini, E
Louis, LS
Antony, J
Karali, E
Okon, IS
McKie, AB
Vaughan, S
El-Bahrawy, M
Stebbing, J
Recchi, C
Gabra, H
Item Type: Journal Article
Abstract: OPCML is a tumor suppressor gene that is frequently inactivated in ovarian cancer and many other cancers by somatic methylation. We have previously shown that OPCML exerts its suppressor function by negatively regulating a spectrum of receptor tyrosine kinases (RTKs), such as ErbB2/HER2, FGFR1 and EphA2, thus attenuating their related downstream signaling. The physical interaction of OPCML with this defined group of RTKs is a prerequisite for their downregulation. Overexpression/gene amplification of EGFR and HER2 is a frequent event in multiple cancers including ovarian and breast cancers. Molecular therapeutics against EGFR/HER2 or EGFR only, such as lapatinib and erlotinib respectively, were developed to target these receptors but resistance often occurs in relapsing cancers. Here we show that, though OPCML interacts only with HER2 and not with EGFR, the interaction of OPCML with HER2 disrupts the formation of the HER2-EGFR heterodimer and this translates into a better response to both lapatinib and erlotinib in HER2-expressing ovarian and breast cancer cell lines. Also, we show that high OPCML expression is associated with better response to lapatinib therapy in breast cancer patients and better survival in HER2-overexpressing ovarian cancer patients, suggesting that OPCML co-therapy could be a valuable sensitizing approach to RTK inhibitors.
Issue Date: 3-Aug-2017
Date of Acceptance: 14-Jul-2017
URI: http://hdl.handle.net/10044/1/50126
DOI: https://dx.doi.org/10.1158/1535-7163.MCT-17-0081
ISSN: 1535-7163
Publisher: American Association for Cancer Research
Start Page: 2246
End Page: 2256
Journal / Book Title: Molecular Cancer Therapeutics
Volume: 16
Issue: 10
Copyright Statement: Copyright ©2017, American Association for Cancer Research. The tumor suppressor protein OPCML potentiates anti-EGFR and anti-HER2 targeted therapy in HER2-positive ovarian and breast cancer Elisa Zanini, Louay S. Louis, Jane Antony, Evdoxia Karali, Imoh S. Okon, Arthur B. McKie, Sebastian Vaughan, Mona El-Bahrawy, Justin Stebbing, Chiara Recchi and Hani Gabra Mol Cancer Ther August 3 2017 DOI: 10.1158/1535-7163.MCT-17-0081
Sponsor/Funder: Ovarian Cancer Action
Funder's Grant Number: N/A
Keywords: 1112 Oncology And Carcinogenesis
1115 Pharmacology And Pharmaceutical Sciences
Oncology & Carcinogenesis
Publication Status: Published online
Appears in Collections:Division of Surgery
Division of Cancer
Department of Medicine
Faculty of Medicine



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