The novel MET inhibitor, HQP8361, possesses single agent activity and enhances therapeutic efficacy of AZD9291 (osimertinib) against AZD9291-resistant NSCLC cells with activated MET

• Type of Material: Article
• Authors: Danlei Yu, Central South University; Yiting Li, Central South University; Keven D. Y. Sun, Emory University; Jiajia Gu, Emory University; Zhen Chen, Emory University; Taofeek Owonikoko, Emory University; Suresh Ramalingam, Emory University; Shi-Yong Sun, Emory University
• Language: English
• Date: 2020-01-01
• Publisher: E-CENTURY PUBLISHING CORP
• Publication Version: Final Published Version
• Copyright Statement: © 2020
• License: Creative Commons Attribution-NonCommercial 4.0 International
• Title of Journal or Parent Work: AMERICAN JOURNAL OF CANCER RESEARCH
• Volume: 10
• Issue: 10
• Start Page: 3316
• End Page: 3327
• Grant/Funding Information: his study was supported by NIH/NCI R01 CA223220 (to SYS) and UG1 CA233259 (to SSR, TKO 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. DY and YL are visiting medical students participating in the Xiangya-Emory Visiting Medical Student Program. TKO, SSR and SYS are Georgia Research Alliance Distinguished Cancer Scientists.
• Keywords: HQP8361; GROWTH; ACQUIRED-RESISTANCE; Science & Technology; AMPLIFICATION; AZD9291; Life Sciences & Biomedicine; EGFR; Oncology; LUNG-CANCER; resistance; lung cancer; MET
• Research Categories: Health Sciences, Oncology

Abstract

HQP8361 (MK8033) is a novel and selective MET kinase inhibitor that has completed a phase I clinical trial. AZD9291 (osimertinib) represents the first-approved third generation EGFR-tyrosine kinase inhibitor (EGFR-TKI) for the treatment of non-small cell lung cancer (NSCLC) with activating EGFR mutations and resistant T790M mutation, but faces the giant challenge of acquired resistance developed in patients in the clinic. The current study focuses on determining the activity and mechanism of action of HQP8361 as a single agent and in combination with AZD9291 against human NSCLC cells, particularly those with acquired resistance to AZD9291. The majority of human NSCLC cell lines tested had very low levels of MET and p-MET and were insensitive to HQP8361. However, AZD9291-resistant (AR) cell lines with high levels of MET and p-MET responded to HQP8361 single agent and particularly to the combination of HQP8361 and AZD9291. The HQP8361 and AZD9291 combination synergistically decreased the survival of these HCC827/AR cell lines with enhanced induction of apoptosis that involved alteration of Bim and Mcl-1 levels via modulating their degradation. Moreover, the combination also very effectively inhibited the growth of HCC827/AR xenografts in nude mice. These preclinical findings support the potential of HQP8361 in the treatment of NSCLCs with MET amplification or highly activated MET and, when combined with AZD9291, in overcoming acquired resistance to EGFR-TKIs due to MET amplification.