2. Academic Validation
  3. AXL Mediates Cetuximab and Radiation Resistance Through Tyrosine 821 and the c-ABL Kinase Pathway in Head and Neck Cancer

AXL Mediates Cetuximab and Radiation Resistance Through Tyrosine 821 and the c-ABL Kinase Pathway in Head and Neck Cancer

  • Clin Cancer Res. 2020 Aug 15;26(16):4349-4359. doi: 10.1158/1078-0432.CCR-19-3142.
Nellie K McDaniel 1,  Mari Iida 1,  Kwangok P Nickel 1,  Colin A Longhurst 2,  Samantha R Fischbach 1,  Tamara S Rodems 1,  Carlene A Kranjac 1,  Amber Y Bo 1,  Qianyun Luo 1,  Meghan M Gallagher 1,  Noah B Welke 1,  Kaitlyn R Mitchell 1,  Alison E Schulz 1,  Jaimee C Eckers 1,  Rong Hu 3,  Ravi Salgia 4,  Seungpyo Hong 5 6,  Justine Y Bruce 7 8,  Randall J Kimple 9 8,  Deric L Wheeler 9 8
Affiliations

Affiliations

  • 1 Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
  • 2 Department of Biostatistics and Medical Informatics, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
  • 3 Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
  • 4 Department of Medical Oncology and Experimental Therapeutics, Comprehensive Cancer Center, City of Hope, Duarte, California.
  • 5 Pharmaceutical Sciences Division, University of Wisconsin School of Pharmacy, Madison, Wisconsin.
  • 6 Yonsei Frontier Lab and Department of Pharmacy, Yonsei University, Seoul, Korea.
  • 7 Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
  • 8 University of Wisconsin Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
  • 9 Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin. dlwheeler@wisc.edu rkimple@humonc.wisc.edu.
PMID: 32439698 DOI: 10.1158/1078-0432.CCR-19-3142
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.

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