Inhibition of MEK5/ERK5 signaling overcomes acquired resistance to the third generation EGFR inhibitor, osimertinib, via enhancing Bim-dependent apoptosis. (28th October 2021)

• Record Type: Journal Article
• Authors: Zhao, Wen; Yu, Danlei; Chen, Zhen; Yao, Weilong; Yang, Jin; Ramalingam, Suresh S.; Sun, Shi-Yong
• Is Part Of: Cancer letters. Volume 519(2021)
• Page Start: 141
• Page End: 149
• Publication Date: 2021-10-28
• Subjects: MEK5/ERK5 -- Acquired resistance -- EGFR inhibitors -- Apoptosis -- Lung cancer; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2021.07.007
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: The promising therapeutic efficacy of the third generation EGFR inhibitor, osimertinib (AZD9291), for the treatment of patients with EGFR-mutant non-small cell lung cancer (NSCLC) has been demonstrated in the clinic both as first-line and second line therapy. However, inevitable acquired resistance limits its long-term benefit to patients and is thus a significant clinical challenge. The current study focuses on studying the potential role of targeting MEK5-ERK5 signaling in overcoming acquired resistance to osimertinib. Osimertinib and other third generation EGFR inhibitors exerted a rapid and sustained suppressive effect on ERK5 phosphorylation primarily in EGFR-mutant NSCLC cell lines and lost this activity in some osimertinib-resistant cell lines. Osimertinib combined with either ERK5 or MEK5 inhibitors synergistically decreased the survival of osimertinib-resistant cell lines with enhanced induction of apoptosis primarily via augmenting Bim expression. Moreover, the combination effectively inhibited the growth of osimertinib-resistant xenografts in vivo . Together, these findings suggest the potential role of MEK5-ERK5 signaling in modulating development of acquired resistance to osimertinib and value of targeting this signaling as a potential strategy in overcoming acquired resistance to osimertinib and possibly other third generation EGFR inhibitors. Highlights: Osimertinib effectively suppresses MEK5/ERK5 signaling in EGFR mutant NSCLC cells. Osimertinib losses modulation on this signaling in some osimertinib-resistant cell lines. ERK5 inhibition plus osimertinib augments Bim-dependent apoptosis in the resistant cells. ERK5 inhibition plus osimertinib effectively overcomes osimertinib acquired resistance. Targeting the MEK5/ERK5 may be a novel strategy for overcoming osimertinib acquired resistance.