American Association for Cancer Research
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Figure S3 from MERTK Mediates Intrinsic and Adaptive Resistance to AXL-targeting Agents

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journal contribution
posted on 2023-04-03, 15:09 authored by Nellie K. McDaniel, Christopher T. Cummings, Mari Iida, Justus Hülse, Hannah E. Pearson, Eleana Vasileiadi, Rebecca E. Parker, Rachel A. Orbuch, Olivia J. Ondracek, Noah B. Welke, Grace H. Kang, Kurtis D. Davies, Xiaodong Wang, Stephen V. Frye, H. Shelton Earp, Paul M. Harari, Randall J. Kimple, Deborah DeRyckere, Douglas K. Graham, Deric L. Wheeler

Evaluation of MERTK inhibitor UNC2025


University of Wisconsin Carbone Cancer Center

Wisconsin Head & Neck Cancer SPORE

Vilas Faculty Early Career Investigator Award

NIH SPORE in Lung Cancer

Lung Cancer Colorado Fund




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.

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