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TMEM16A/ANO1 suppression improves response to antibody-mediated targeted therapy of EGFR and HER2/ERBB2
Sucheta Kulkarni1,2, Anke Bill3, Neal R Godse1
1Department of Otolaryngology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
Abstract:
TMEM16A, a Ca2+ -activated Cl- channel, contributes to tumor growth in breast cancer and head and neck squamous cell carcinoma (HNSCC). Here, we investigated whether TMEM16A influences the response to EGFR/HER family-targeting biological therapies. Inhibition of TMEM16A Cl- channel activity in breast cancer cells with HER2 amplification induced a loss of viability. Cells resistant to trastuzumab, a monoclonal antibody targeting HER2, showed an increase in TMEM16A expression and heightened sensitivity to Cl- channel inhibition. Treatment of HNSCC cells with cetuximab, a monoclonal antibody targeting EGFR, and simultaneous TMEM16A suppression led to a pronounced loss of viability. Biochemical analyses of cells subjected to TMEM16A inhibitors or expressing chloride-deficient forms of TMEM16A provide further evidence that TMEM16A channel function may play a role in regulating EGFR/HER2 signaling. These data demonstrate that TMEM16A regulates EGFR and HER2 in growth and survival pathways. Furthermore, in the absence of TMEM16A cotargeting, tumor cells may acquire resistance to EGFR/HER inhibitors. Finally, targeting TMEM16A improves response to biological therapies targeting EGFR/HER family members.
Insights
Targeting TMEM16A, a calcium-activated chloride channel, enhances cancer therapy response. Inhibiting TMEM16A improves outcomes for breast and head and neck cancers treated with EGFR/HER inhibitors.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- TMEM16A (Anoctamin-1) is a calcium-activated chloride channel implicated in tumor growth.
- EGFR/HER family-targeting therapies are crucial in treating breast cancer and head and neck squamous cell carcinoma (HNSCC).
Purpose of the Study:
- To investigate the role of TMEM16A in the efficacy of EGFR/HER-targeted biological therapies.
- To determine if TMEM16A influences therapeutic resistance in cancer.
Main Methods:
- Utilized TMEM16A inhibitors and chloride-deficient TMEM16A variants in cancer cell lines.
- Assessed cell viability and TMEM16A expression in response to targeted therapies (trastuzumab, cetuximab).
- Performed biochemical analyses to elucidate TMEM16A's role in signaling pathways.
Main Results:
- TMEM16A inhibition reduced viability in HER2-amplified breast cancer cells and HNSCC cells treated with EGFR inhibitors.
- Trastuzumab-resistant cells exhibited increased TMEM16A expression and sensitivity to TMEM16A inhibition.
- TMEM16A channel function is linked to EGFR/HER2 signaling, impacting cancer cell growth and survival.
Conclusions:
- TMEM16A plays a critical role in regulating EGFR and HER2 signaling pathways.
- Co-targeting TMEM16A with EGFR/HER inhibitors can overcome or prevent therapeutic resistance.
- Targeting TMEM16A represents a promising strategy to enhance the effectiveness of biological therapies against EGFR/HER family members.
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