Overcoming acquired resistance of EGFR-mutant NSCLC cells to the third generation EGFR inhibitor, osimertinib, with the natural product honokiol

• Type of Material: Article
• Authors: Hongjing Zang, Emory University; Guo Qian, Emory University; Jack Arbiser, Emory University; Taofeek Owonikoko, Emory University; Suresh Ramalingam, Emory University; Songqing Fan, Central South University; Shi-Yong Sun, Emory University
• Language: English
• Date: 2020-02-14
• Publisher: Wiley
• Publication Version: Final Published Version
• Copyright Statement: © 2020 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1002/1878-0261.12645
• Title of Journal or Parent Work: Molecular Oncology
• Volume: 14
• Issue: 4
• Start Page: 882
• End Page: 895
• Grant/Funding Information: Lee Foundation Award to the Winship Lung Cancer Program for supporting the pilot project; Emory Winship Cancer Institute lung cancer research pilot funds (to SYS)
• Keywords: Lung cancer; Life Sciences & Biomedicine; Protein; Apoptosis; Osimertinib; EGFR; Acquired resistance; Oncology; Activation; Science & Technology; Metastasis; BIM; Honokiol; Growth
• Research Categories: Health Sciences, Oncology; Biology, Molecular; Health Sciences, Pharmacology

Abstract

The development of acquired resistance to osimertinib (Osim) (AZD9291 or TAGRISSOTM), an FDA-approved third-generation epidermal growth factor receptor (EGFR) inhibitor for the treatment of EGFR-mutant nonsmall cell lung cancer (NSCLC), limits the long-term benefits for patients. Thus, effective treatment options are urgently needed. To this end, we explored whether honokiol (HNK), a natural product with potential antitumor activity, may be used to overcome Osim resistance. The combination of HNK and Osim synergistically decreased the survival of several Osim -resistant cell lines with enhanced effects on inhibiting cell colony formation and growth and on inducing apoptosis. This combination also showed greater growth suppression of Osim-resistant xenograft tumors including those with 19del, T790M, and C797S triple mutations in nude mice. Mechanistically, the augmented induction of apoptosis by the combination is largely due to enhanced Mcl-1 reduction through facilitating its degradation. A synthetic HNK derivative exerted similar effects with greater efficacy. Our findings warrant further study of HNK and its derivatives in overcoming Osim resistance in the clinic.