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MERTK Promotes Resistance to Irreversible EGFR Tyrosine Kinase Inhibitors in Non–small Cell Lung Cancers Expressing Wild-type EGFR Family Members
- Source :
- Clinical Cancer Research. 24:6523-6535
- Publication Year :
- 2018
- Publisher :
- American Association for Cancer Research (AACR), 2018.
-
Abstract
- Purpose: Lung cancer is the leading cause of cancer-related death. Non–small cell lung cancer (NSCLC) accounts for 85% of all lung cancers and over 60% express wild-type EGFR (wtEGFR); however, EGFR tyrosine kinase inhibitors (TKIs) have limited effect in most patients with wtEGFR tumors. We previously identified MERTK tyrosine kinase as a potential therapeutic target in NSCLC and developed MRX-2843, a novel MERTK-selective inhibitor with favorable properties for clinical translation. The goal of this study was to determine whether MERTK and EGFR inhibitor combination therapy could provide antitumor efficacy against wtEGFR NSCLC. Experimental Design: An unbiased screen of 378 kinase inhibitors was conducted to identify synergistic interactions with MRX-2843 and biochemical and therapeutic effects were determined in vitro and in vivo. Results: Numerous irreversible EGFR TKIs, including CO-1686 and osimertinib, synergized with MRX-2843 to inhibit wtEGFR NSCLC cell expansion, irrespective of driver oncogene status. CO-1686 and MRX-2843 combination therapy inhibited MERTK, wtEGFR, and ERBB2/ERBB3 and decreased downstream PI3K-AKT, MAPK-ERK, and AURORA kinase (AURK) signaling more effectively than single agents. Inhibition of PI3K, AKT or AURK, but not MEK, synergized with CO-1686 to inhibit tumor cell expansion, suggesting their roles as key redundant resistance pathways. Treatment with MRX-2843 and CO-1686 or osimertinib prevented xenograft growth while single agents had limited effect. Tumor growth inhibition was durable even after treatment with combination therapy was stopped. Conclusions: Our data support the application of MRX-2843 in combination with an irreversible EGFR TKI as a novel strategy for treatment of patients with wtEGFR NSCLC.
- Subjects :
- 0301 basic medicine
Cancer Research
business.industry
MERTK
medicine.disease
respiratory tract diseases
03 medical and health sciences
030104 developmental biology
0302 clinical medicine
Aurora kinase
Oncology
030220 oncology & carcinogenesis
Cancer research
medicine
ERBB3
Osimertinib
Lung cancer
business
Protein kinase B
Tyrosine kinase
EGFR inhibitors
Subjects
Details
- ISSN :
- 15573265 and 10780432
- Volume :
- 24
- Database :
- OpenAIRE
- Journal :
- Clinical Cancer Research
- Accession number :
- edsair.doi...........b5059fdcac9180b7ab998f926815b702