Targeting Transient Receptor Potential Melastatin‐2 (TRPM2) Enhances Therapeutic Efficacy of Third Generation EGFR Inhibitors against EGFR Mutant Lung Cancer

There is an urgent need to fully understand the biology of third generation EGFR‐tyrosine kinase inhibitors (EGFR‐TKIs), particularly osimertinib, and to develop mechanism‐driven strategies to manage their acquired resistance. Transient receptor potential melastatin‐2 (TRPM2) functions as an important regulator of Ca2+ influx, but its role in mediating therapeutic efficacies of EGFR‐TKIs and acquired resistance to EGFR‐TKIs has been rarely studied. This study has demonstrated a previously undiscovered role of suppression of TRPM2 and subsequent inhibition of Ca2+ influx and induction of ROS and DNA damage in mediating apoptosis induction and the therapeutic efficacy of osimertinib against EGFR mutant NSCLC. The rebound elevation represents a key mechanism accounting for the emergence of acquired resistance to osimertinib and other third generation EGFR‐TKIs. Accordingly, targeting TRPM2 is a potentially promising strategy for overcoming and preventing acquired resistance to osimertinib, warranting further study in this direction including the development of cancer therapy‐optimized TRPM2 inhibitors. This study reveals a previously undiscovered role of suppression of TRPM2, an important regulator of Ca2+ influx, in mediating therapeutic efficacy of osimertinib against EGFR mutant non‐small cell lung cancer and suggests targeting TRPM2 as a potentially promising strategy for managing acquired resistance to osimertinib and other third generation EGFR inhibitors.