1. Academic Validation
  2. Targeting Transient Receptor Potential Melastatin-2 (TRPM2) Enhances Therapeutic Efficacy of Third Generation EGFR Inhibitors against EGFR Mutant Lung Cancer

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

  • Adv Sci (Weinh). 2024 Jul 23:e2310126. doi: 10.1002/advs.202310126.
Zhen Chen 1 Karin A Vallega 1 Vijay K Boda 2 Zihan Quan 3 Dongsheng Wang 1 Songqing Fan 3 Qiming Wang 4 Suresh S Ramalingam 1 Wei Li 2 Shi-Yong Sun 1
Affiliations

Affiliations

  • 1 Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, GA, 30047, USA.
  • 2 Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN, 38163, USA.
  • 3 Department of Pathology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, P. R. China.
  • 4 Department of Internal Medicine, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, 450008, P. R. China.
Abstract

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.

Keywords

EGFR‐TKIs; TRPM2; apoptosis; calcium; lung cancer; osimertinib.

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