ERK inhibition effectively overcomes acquired resistance of epidermal growth factor receptor-mutant non-small-cell lung cancer cells to osimertinib

• Type of Material: Article
• Authors: Yiting Li, Central South University China; Hongjing Zang, Central South University, Changsha; Guoqing Qian, Emory University; Taofeek Owonikoko, Emory University; Suresh Ramalingam, Emory University; Shi-Yong Sun, Emory University
• Language: English
• Date: 2019-12-10
• Publisher: WILEY
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2019 American Cancer Society
• Final Published Version (URL): http://dx.doi.org/10.1002/cncr.32655
• Title of Journal or Parent Work: CANCER
• Volume: 126
• Issue: 6
• Start Page: 1339
• End Page: 1350
• Grant/Funding Information: NIH/NCI R01 CA223220 (to SYS) and UG1 CA233259 (to SSR and SYS), Emory Winship Cancer Institute lung cancer research pilot funds (to SYS) and Lee Foundation Award to the Winship Lung Cancer Program for supporting the pilot project
• Keywords: MCL-1; ERK; EXPRESSION; Life Sciences & Biomedicine; Science & Technology; epidermal growth factor receptor (EGFR); lung cancer; resistance; osimertinib; MEK; Oncology

Abstract

Background: Osimertinib (AZD9291), a third-generation, mutation-selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (EGFR-TKI), is an approved drug for patients who have non–small cell lung cancer (NSCLC) with activating EGFR mutations or those harboring a resistant T790M mutation. Unfortunately, all patients eventually relapse and develop resistance to osimertinib. The current study addressed whether ERK inhibition exerts effects similar to those produced by MEK inhibition in overcoming acquired resistance to osimertinib. Methods: Drug effects on cell and tumor growth were assessed by measuring cell number alterations and colony formation in vitro and with xenografts in nude mice in vivo. Apoptosis was assessed with annexin V/flow cytometry and protein cleavage. Protein alterations in cells were detected with Western blot analysis. Gene overexpression and knockout were achieved with lentiviral infection and CRISPR/Cas9, respectively. Results: The combination of osimertinib with an ERK inhibitor synergistically decreased the survival of osimertinib-resistant cell lines with enhanced induction of apoptosis and effectively inhibited the growth of osimertinib-resistant xenografts in nude mice. Moreover, the combination of an MEK or ERK inhibitor with a first-generation (eg, erlotinib) or second-generation (eg, afatinib) EGFR-TKI also very effectively inhibited the growth of osimertinib-resistant cells in vitro and of tumors in vivo, although these cell lines were cross-resistant to first-generation or second-generation EGFR-TKIs. Conclusions: The current findings emphasize the importance of targeting MEK/ERK signaling in maintaining the long-term benefit of osimertinib through overcoming acquired resistance to osimertinib, warranting further investigation of this therapeutic strategy to improve the therapeutic efficacy of osimertinib in the clinic.