2. Academic Validation
  3. 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.
PMID: 39044361 DOI: 10.1002/advs.202310126
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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