1. AXL Mediates Cetuximab and Radiation Resistance Through Tyrosine 821 and the c-ABL Kinase Pathway in Head and Neck Cancer
- Author
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Samantha R. Fischbach, Kaitlyn R. Mitchell, Seungpyo Hong, Tamara S. Rodems, Deric L. Wheeler, Alison E. Schulz, Jaimee C. Eckers, Ravi Salgia, Qianyun Luo, Colin Longhurst, Noah B. Welke, Justine Yang Bruce, Nellie K. McDaniel, Carlene A. Kranjac, Amber Bo, Randall J. Kimple, Kwangok P. Nickel, Rong Hu, Meghan M. Gallagher, and Mari Iida
- Subjects
0301 basic medicine ,Proteomics ,Cancer Research ,Cetuximab ,Context (language use) ,Genes, abl ,Radiation Tolerance ,Receptor tyrosine kinase ,Article ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Cell Line, Tumor ,Proto-Oncogene Proteins ,medicine ,Animals ,Humans ,neoplasms ,ABL ,biology ,business.industry ,Head and neck cancer ,Receptor Protein-Tyrosine Kinases ,medicine.disease ,Head and neck squamous-cell carcinoma ,Xenograft Model Antitumor Assays ,Axl Receptor Tyrosine Kinase ,Gene Expression Regulation, Neoplastic ,030104 developmental biology ,Oncology ,Drug Resistance, Neoplasm ,Head and Neck Neoplasms ,030220 oncology & carcinogenesis ,biology.protein ,Cancer research ,Tyrosine ,Signal transduction ,Neoplasm Recurrence, Local ,business ,Tyrosine kinase ,medicine.drug ,Signal Transduction - Abstract
Purpose: Radiation and cetuximab are therapeutics used in management of head and neck squamous cell carcinoma (HNSCC). Despite clinical success with these modalities, development of both intrinsic and acquired resistance is an emerging problem in the management of this disease. The purpose of this study was to investigate signaling of the receptor tyrosine kinase AXL in resistance to radiation and cetuximab treatment. Experimental Design: To study AXL signaling in the context of treatment-resistant HNSCC, we used patient-derived xenografts (PDXs) implanted into mice and evaluated the tumor response to AXL inhibition in combination with cetuximab or radiation treatment. To identify molecular mechanisms of how AXL signaling leads to resistance, three tyrosine residues of AXL (Y779, Y821, Y866) were mutated and examined for their sensitivity to cetuximab and/or radiation. Furthermore, reverse phase protein array (RPPA) was employed to analyze the proteomic architecture of signaling pathways in these genetically altered cell lines. Results: Treatment of cetuximab- and radiation-resistant PDXs with AXL inhibitor R428 was sufficient to overcome resistance. RPPA analysis revealed that such resistance emanates from signaling of tyrosine 821 of AXL via the tyrosine kinase c-ABL. In addition, inhibition of c-ABL signaling resensitized cells and tumors to cetuximab or radiotherapy even leading to complete tumor regression without recurrence in head and neck cancer models. Conclusions: Collectively, the studies presented herein suggest that tyrosine 821 of AXL mediates resistance to cetuximab by activation of c-ABL kinase in HNSCC and that targeting of both EGFR and c-ABL leads to a robust antitumor response.
- Published
- 2019