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

Elisa Zanini1, Louay S Louis1, Jane Antony1

  • 1Ovarian Cancer Action Research Centre, Department of Surgery and Cancer, Imperial College London, London, United Kingdom.

Molecular Cancer Therapeutics
|August 5, 2017
PubMed

Insights

Opioid-binding protein/cell adhesion molecule-like (OPCML) suppresses tumors by regulating receptor tyrosine kinases. High OPCML expression improves response to cancer therapies targeting HER2 and EGFR, suggesting its potential as a co-therapy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Genetics

Background:

  • Opioid-binding protein/cell adhesion molecule-like (OPCML) is a tumor suppressor gene frequently inactivated in various cancers via methylation.
  • OPCML negatively regulates receptor tyrosine kinases (RTKs) like HER2, FGFR1, and EphA2, attenuating downstream signaling.
  • Overexpression of EGFR and HER2 is common in ovarian and breast cancers, and resistance to targeted therapies like lapatinib and erlotinib is a clinical challenge.

Purpose of the Study:

  • To investigate the role of OPCML in regulating HER2-EGFR heterodimerization and its impact on response to RTK inhibitors.
  • To determine if OPCML expression correlates with patient response to lapatinib therapy and survival outcomes in HER2-overexpressing cancers.

Main Methods:

  • Cell line experiments to assess OPCML interaction with HER2 and EGFR.
  • Analysis of HER2-EGFR heterodimer formation in the presence of OPCML.
  • Evaluation of cancer cell line response to lapatinib and erlotinib.
  • Retrospective analysis of breast cancer patient data for lapatinib response and ovarian cancer patient data for survival based on OPCML expression.

Main Results:

  • OPCML interacts with HER2 but not EGFR, disrupting HER2-EGFR heterodimer formation.
  • OPCML expression enhances the efficacy of lapatinib and erlotinib in HER2-expressing ovarian and breast cancer cell lines.
  • High OPCML expression is associated with improved response to lapatinib in breast cancer patients and better survival in HER2-overexpressing ovarian cancer patients.

Conclusions:

  • OPCML plays a critical role in inhibiting HER2-EGFR signaling pathways.
  • OPCML expression is a predictive biomarker for response to HER2-targeted therapies.
  • OPCML co-therapy represents a promising strategy to overcome resistance to RTK inhibitors in cancer treatment.

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