MERTK Mediates Intrinsic and Adaptive Resistance to AXL-targeting Agents

• Type of Material: Article
• Authors: Nellie K. McDaniel, University of Wisconsin; Christopher T. Cummings, University of Colorado; Mari Iida, University of Wisconsin; Justus Hulse, Emory University; Hannah E. Pearson, University of Wisconsin; Eleana Vasileiadi, Emory University; Rebecca E. Parker, Emory University; Rachel A. Orbuch, University of Wisconsin; Olivia J. Ondracek, University of Wisconsin; Noah B. Welke, University of Wisconsin; Grace Hye-Hyun Kang, University of Wisconsin; Kurtis D. Davies, University of Colorado; Xiaodong Wang, University of North Carolina Chapel Hill; Stephen V. Frye, University of North Carolina Chapel Hill; H. Shelton Earp, Lineberger Comprehensive Cancer Center; Paul M. Harari, University of Wisconsin; Randall J. Kimple, University of Wisconsin; Deborah DeRyckere, Emory University; Douglas Graham, Emory University; Deric L. Wheeler, University of Wisconsin
• Language: English
• Date: 2018-11-01
• Publisher: AMER ASSOC CANCER RESEARCH
• Publication Version: Final Published Version
• Copyright Statement: © 2018 American Association for Cancer Research.
• Final Published Version (URL): http://dx.doi.org/10.1158/1535-7163.MCT-17-1239
• Title of Journal or Parent Work: MOLECULAR CANCER THERAPEUTICS
• Volume: 17
• Issue: 11
• Start Page: 2297
• End Page: 2308
• Grant/Funding Information: Research reported in this publication was supported by the Wisconsin Head & Neck Cancer SPORE (DLW, RJK, and PMH P50 DE026787), Vilas Faculty Early Career Investigator Award (DLW, MSN189325), an NIH SPORE in Lung Cancer grant (KDD, P50CA058187), the Lung Cancer Colorado Fund (KDD) and an NIH grant from Cellular and Molecular Pathology Graduate Training Program (NKM, 5 T32 GM81061–7).
• Keywords: EGFR; TUMOR-GROWTH; MESENCHYMAL TRANSITION; PREDICTS; EXPRESSION; CELL LUNG-CANCER; SMALL-MOLECULE INHIBITOR; Oncology; ACQUIRED-RESISTANCE; Life Sciences & Biomedicine; THERAPEUTIC TARGET; RECEPTOR TYROSINE KINASES; Science & Technology
• Research Categories: Health Sciences, Oncology

Abstract

The TAM (TYRO3, AXL, MERTK) family receptor tyrosine kinases (RTK) play an important role in promoting growth, survival, and metastatic spread of several tumor types. AXL and MERTK are overexpressed in head and neck squamous cell carcinoma (HNSCC), triple-negative breast cancer (TNBC), and non-small cell lung cancer (NSCLC), malignancies that are highly metastatic and lethal. AXL is the most well-characterized TAM receptor and mediates resistance to both conventional and targeted cancer therapies. AXL is highly expressed in aggressive tumor types, and patients with cancer are currently being enrolled in clinical trials testing AXL inhibitors. In this study, we analyzed the effects of AXL inhibition using a small-molecule AXL inhibitor, a monoclonal antibody (mAb), and siRNA in HNSCC, TNBC, and NSCLC preclinical models. Anti-AXL-targeting strategies had limited efficacy across these different models that, our data suggest, could be attributed to upregulation of MERTK. MERTK expression was increased in cell lines and patient-derived xenografts treated with AXL inhibitors and inhibition of MERTK sensitized HNSCC, TNBC, and NSCLC preclinical models to AXL inhibition. Dual targeting of AXL and MERTK led to a more potent blockade of downstream signaling, synergistic inhibition of tumor cell expansion in culture, and reduced tumor growth in vivo. Furthermore, ectopic overexpression of MERTK in AXL inhibitor-sensitive models resulted in resistance to AXL-targeting strategies. These observations suggest that therapeutic strategies cotargeting both AXL and MERTK could be highly beneficial in a variety of tumor types where both receptors are expressed, leading to improved survival for patients with lethal malignancies. Mol Cancer Ther; 17(11); 2297-308. 2018 AACR.