Reactivation of mutant-EGFR degradation through clathrin inhibition overcomes resistance to EGFR tyrosine kinase inhibitors.

Tyrosine kinase inhibitors (TKIs) targeting mutant-EGFR in NSCLC have been successful to control cancer growth, but acquired resistance inevitably occurs, including mutations directly on EGFR e.g. T790M and C797S. Strategies to prevent such acquired mutations by reducing mutant-EGFR expression have met limited success. Here we propose a new model of mutant-EGFR trafficking and demonstrate that clathrin inhibition induces rapid degradation across a large panel of endogenous mutant-EGFR (Ex19del, L858R, Ex20Ins). This panel included mutant-EGFR (T790M) resistant to the first- and second-generation EGFR inhibitors and to the third-generation TKI osimertinib, and occurs through both mutational (C797S) and non-mutational EGFR mechanisms. Clathrin-mediated endocytosis inhibition of mutant-EGFR induced a macropinocytosis-dependent lysosomal pathway associated with a loss of mutant-EGFR dependent signalling (pAKT, pERK). Moreover, induction of this macropinocytic pathway led to robust apoptosis-dependent death across all mutant-EGFR cell lines tested, including those resistant to TKIs. We therefore propose a novel strategy to target mutant-EGFR refractory to approved existing TKI treatments in NSCLC and where new treatment strategies remain a key area of unmet need.

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