1. Academic Validation
  2. Inhibition of hTERT/telomerase/telomere mediates therapeutic efficacy of osimertinib in EGFR mutant lung cancer

Inhibition of hTERT/telomerase/telomere mediates therapeutic efficacy of osimertinib in EGFR mutant lung cancer

  • J Exp Med. 2024 Nov 4;221(11):e20240435. doi: 10.1084/jem.20240435.
Zhen Chen 1 Karin A Vallega 1 Dongsheng Wang 1 Zihan Quan 2 Songqing Fan 2 Qiming Wang 3 Ticiana Leal 1 Suresh S Ramalingam 1 Shi-Yong Sun 1
Affiliations

Affiliations

  • 1 Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, GA, USA.
  • 2 Department of Pathology, The Second Xiangya Hospital, Central South University, Changsha, China.
  • 3 Department of Internal Medicine, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China.
Abstract

The inevitable acquired resistance to osimertinib (AZD9291), an FDA-approved third-generation EGFR tyrosine kinase inhibitor (EGFR-TKI) for the treatment of patients with advanced non-small cell lung Cancer (NSCLC) harboring EGFR activating or T790M resistant mutations, limits its long-term clinical benefit. Telomere maintenance via Telomerase reactivation is linked to uncontrolled cell growth and is a Cancer hallmark and an attractive Cancer therapeutic target. Our effort toward understanding the action mechanisms, including resistance mechanisms, of osimertinib has led to the identification of a novel and critical role in maintaining c-Myc-dependent downregulation of hTERT, a catalytic subunit of Telomerase, and subsequent inhibition of Telomerase/telomere and induction of telomere dysfunction in mediating therapeutic efficacy of osimertinib. Consequently, osimertinib combined with the telomere inhibitor, 6-Thio-dG, which is currently tested in a phase II trial, effectively inhibited the growth of osimertinib-resistant tumors, regressed EGFRm NSCLC patient-derived xenografts, and delayed the emergence of acquired resistance to osimertinib, warranting clinical validation of this strategy to manage osimertinib acquired resistance.

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