About this item:

114 Views | 43 Downloads

Author Notes:

Douglas K. Graham, AFLAC Cancer and Blood Disorders Center, 2015 Uppergate Drive, Atlanta, Georgia 30322, USA. Phone: 404.785.3874; Email: douglas.graham@choa.org

DY conceived the study, designed, performed, analyzed, and interpreted experiments, and wrote the manuscript. DKG and DD conceived the study, analyzed and interpreted experiments, and edited the manuscript. JMH performed and analyzed experiments. DK designed, performed, analyzed, and interpreted computational modeling. ZT, LC, and SG analyzed experiments. MB and FS provided patient samples and related clinical data. HSE, XW, and SVF provided suggestions for experiments and edited the manuscript. SSR and TO provided suggestions for experiments and clinical perspective and edited the manuscript. All authors read and agreed with the manuscript

This research was supported by the National Cancer Institute (NCI) of the National Institutes of Health (Emory University Lung Cancer SPORE, P50CA217691), Winship Cancer Institute #IRG-17-181-05 from the American Cancer Society, the Emory Lung SPORE Pathology Core, and the Winship Cancer Institute Biostatistics and Cancer Tissue and Pathology Shared Resources (P30CA138292). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The authors thank Rebecca Parker and Travon Baxter for technical support during animal studies and Arlen Ho for providing preliminary data related to this work.

DKG, SVF, and HSE are founders of Meryx Inc. DKG and SVF serve on the Board of Directors of Meryx Inc. SVF, HSE, DKG, DD, and XW are equity holders in Meryx Inc. The company’s key clinical candidate, MRX-2843, is evaluated in this research. XW and SVF are inventors on patents describing MRX-2843 (patent numbers listed in Supplemental Materials). DY, HSE, DD, and DKG are inventors on a patent (number US10709708B2 [to Emory University]) describing the use of MRX-2843 in combination with osimertinib. SSR has served on the Scientific Advisory Board and in a consulting role for AstraZenca and has also received research support (to Emory University) from AstraZeneca. TO has received research funding (to Emory University) from AstraZeneca in compensation for advisory board service.

Subjects:

Research Funding:

The data included in this manuscript are the major data used for the funded Emory Lung Cancer Spore (P50CA217691) of Project 2.

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Medicine, Research & Experimental
  • Research & Experimental Medicine
  • RECEPTOR-TYROSINE KINASE
  • MOLECULAR-DYNAMICS
  • AXL KINASE
  • MUTATIONS
  • INHIBITORS
  • GEFITINIB
  • MODELS
  • DOCETAXEL
  • SURVIVAL
  • THERAPY

MERTK activation drives osimertinib resistance in EGFR-mutant non small cell lung cancer

Show all authors Show less authors

Tools:

Journal Title:

JOURNAL OF CLINICAL INVESTIGATION

Volume:

Volume 132, Number 15

Publisher:

Type of Work:

Article | Final Publisher PDF

Abstract:

Acquired resistance is inevitable in non-small cell lung cancers (NSCLCs) treated with osimertinib (OSI), and the mechanisms are not well defined. The MERTK ligand GAS6 promoted downstream oncogenic signaling in EGFR-mutated (EGFRMT) NSCLC cells treated with OSI, suggesting a role for MERTK activation in OSI resistance. Indeed, treatment with MRX-2843, a firstin- class MERTK kinase inhibitor, resensitized GAS6-treated NSCLC cells to OSI. Both GAS6 and EGF stimulated downstream PI3K/AKT and MAPK/ERK signaling in parental cells, but only GAS6 activated these pathways in OSI-resistant (OSIR) derivative cell lines. Functionally, OSIR cells were more sensitive to MRX-2843 than parental cells, suggesting acquired dependence on MERTK signaling. Furthermore, MERTK and/or its ligands were dramatically upregulated in EGFRMT tumors after treatment with OSI in both xenograft models and patient samples, consistent with induction of autocrine/paracrine MERTK activation. Moreover, treatment with MRX-2843 in combination with OSI, but not OSI alone, provided durable suppression of tumor growth in vivo, even after treatment was stopped. These data identify MERTK as a driver of bypass signaling in treatment-naive and EGFRMT-OSIR NSCLC cells and predict that MRX-2843 and OSI combination therapy will provide clinical benefit in patients with EGFRMT NSCLC.

Copyright information:

© 2022, Yan et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
Export to EndNote