EGFR signaling in breast cancer requires licensing from separate membrane nanodomains

Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase with numerous roles in maintaining cell physiology; it is upregulated in many cancers, including breast cancer, where it contributes to tumor growth and metastasis. This feature of EGFR signaling in cancer has prompted the development of anti‐EGFR therapies. However, many cancers, while initially responsive to anti‐EGFR therapies, develop resistance to prolonged treatment, which imposes a significant challenge in applying anti‐EGFR therapies to the treatment of difficult to treat cancers such as triple negative breast cancer. Resistance to anti‐EGFR therapy is not a consequence of EGFR mutation, and instead it has been speculated that alterations in EGFR plasma membrane confinement within specialized membrane nanodomains contributes to aberrant signaling in cancer. We previously reported that EGFR activation of downstream Akt signaling requires clathrin nanodomains; the contribution of other nanodomains (flotillins, tetraspanins, caveolae, etc.) to EGFR signaling remains unknown. To probe EGFR signaling in membrane nanodomains we developed tools to track EGFR, EGF‐ligand, and various nanodomains at the single molecule level by dual‐colour, live‐cell TIRF microscopy coupled with MATLAB automated detection and particle analysis. Treatment of breast cancer cell lines with EGFR tyrosine kinase inhibitors (TKI) attenuated EGFR confinement within clathrin nanodomains and subsequent Akt signaling, but only in cell lines sensitive to the cytotoxic effects of the drugs. Interestingly, mobilization of EGFR to clathrin following stimulation with EGF‐ligand required PKC activation and confinement within non‐clathrin nanodomains, a feature that was altered in EGFR TKI‐resistant breast cancer cells. This two nanodomain model of EGFR activation resolves some longstanding, unexplained features of EGFR signaling, such the inability of the majority of EGFR to bind ligand and suggests that EGFR licensing by membrane nanodomains is a critical regulator of EGFR signaling that contributes to therapeutic resistance. Ongoing work will determine the mechanism that links EGFR licensing between membrane nanodomains, EGFR signaling, and drug resistance in breast cancer. Support or Funding Information CIHR PJT‐156355 to GDF and CNA

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