Managing acquired resistance to third-generation egfr tyrosine kinase inhibitors through co-targeting mek/erk signaling

• Type of Material: Article
• Authors: Danlei Yu, Central South University; Wen Zhao, Emory University; Karin A. Vallega, Emory University School of Medicine; Shi-Yong Sun, Emory University
• Language: English
• Date: 2021-01-01
• Publisher: Dovepress
• Publication Version: Final Published Version
• Copyright Statement: © 2021 Yu et al.
• License: Creative Commons Attribution-Noncommercial 3.0 Unported
• Final Published Version (URL): http://dx.doi.org/10.2147/LCTT.S293902
• Title of Journal or Parent Work: Lung Cancer: Targets and Therapy
• Volume: 12
• Start Page: 1
• End Page: 10
• Grant/Funding Information: SYS is a Georgia Research Alliance Distinguished Cancer Scientist and supported by NIH/NCI R01 CA223220 (to SYS), R01 CA245386 (to SYS), UG1 CA233259 and Lung Cancer SPORE P50 CA217691 DRP award (to S-YS) and Emory University Winship Cancer Institute lung cancer pilot fund (to SYS).
• Keywords: MEK/ERK; acquired resistance; lung cancer; EGFR inhibitors; osimertinib
• Research Categories: Health Sciences, Medicine and Surgery; Health Sciences, Oncology

Abstract

Although epidermal growth factor receptor (EGFR)-targeted therapy has improved clinical outcomes of patients with advanced non-small-cell lung cancer (NSCLC) carrying activating EGFR mutations, the development of acquired resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs), including the promising third-generation ones, results in disease progression and has become an unavoidable problem that limits patient long-term benefit. The third-generation EGFR-TKIs, osimertinib and almonertinib, are now approved for the treatment of advanced NSCLC patients harboring activating EGFR mutations (first-line) and/or the resistant T790M mutation (second-line). Clinically, appropriate management of acquired resistance to third-generation EGFR-TKIs will substantially improve their long-term efficacy against EGFR-mutant NSCLC. Recent preclinical and clinical studies suggest that activation of the Ras/ Raf/MEK/ERK signaling pathway may be an important resistance mechanism and accordingly co-targeting this pathway effectively overcomes and abrogates acquired resistance to third-generation EGFR-TKIs. This review focuses on discussing the scientific rationale for and potential of co-targeting MEK/ERK signaling in delaying and overcoming acquired resistance to third-generation EGFR-TKIs, particularly osimertinib.