The Tumor-Suppressor Protein OPCML Potentiates Anti–EGFR- and Anti–HER2-Targeted Therapy in HER2-Positive Ovarian and Breast Cancer

Autor: Elisa Zanini, Louay S. Louis, Hani Gabra, Mona El-Bahrawy, Chiara Recchi, Justin Stebbing, Evdoxia Karali, Arthur B. McKie, Imoh Okon, Jane Antony, Sebastian Vaughan
Přispěvatelé: Ovarian Cancer Action
Rok vydání: 2017
Předmět:
0301 basic medicine
Cancer Research
Receptor
ErbB-2
medicine.medical_treatment
Breast Neoplasms
GPI-Linked Proteins
Lapatinib
Receptor tyrosine kinase
Targeted therapy
Erlotinib Hydrochloride
03 medical and health sciences
Breast cancer
Cell Line
Tumor
medicine
Humans
Oncology & Carcinogenesis
Molecular Targeted Therapy
skin and connective tissue diseases
Protein Kinase Inhibitors
neoplasms
Ovarian Neoplasms
biology
Gene Amplification
Cancer
Trastuzumab
medicine.disease
EPH receptor A2
ErbB Receptors
Gene Expression Regulation
Neoplastic
030104 developmental biology
Oncology
Immunology
Quinazolines
biology.protein
Cancer research
1115 Pharmacology And Pharmaceutical Sciences
Female
Erlotinib
Neoplasm Recurrence
Local
Ovarian cancer
1112 Oncology And Carcinogenesis
Cell Adhesion Molecules
medicine.drug
Zdroj: Molecular Cancer Therapeutics. 16:2246-2256
ISSN: 1538-8514
1535-7163
DOI: 10.1158/1535-7163.mct-17-0081
Popis: Opioid-binding protein/cell adhesion molecule-like (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 (RTK), 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. Mol Cancer Ther; 16(10); 2246–56. ©2017 AACR.
Databáze: OpenAIRE
Externí odkaz: