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Ref Type Journal Article
PMID (32439698)
Authors McDaniel NK, Iida M, Nickel KP, Longhurst CA, Fischbach SR, Rodems TS, Kranjac CA, Bo AY, Luo Q, Gallagher MM, Welke NB, Mitchell KR, Schulz AE, Eckers JC, Hu R, Salgia R, Hong S, Bruce JY, Kimple RJ, Wheeler DL
Title AXL Mediates Cetuximab and Radiation Resistance Through Tyrosine 821 and the c-ABL Kinase Pathway in Head and Neck Cancer.
Journal Clinical cancer research : an official journal of the American Association for Cancer Research
Vol 26
Issue 16
Date 2020 Aug 15
URL
Abstract Text 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.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.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.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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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
AXL Y779F missense unknown AXL Y779F lies within the protein kinase domain of the Axl protein (UniProt.org). Y779F demonstrates similar binding to Abl2 in the presence of ligand in cell culture (PMID: 31825826) and confers resistance Erbitux (cetuximab) in cell culture (PMID: 32439698), but has not been fully biochemically characterized and therefore, its effect on Axl protein function is unknown. Y
AXL Y866F missense no effect - predicted AXL Y866F lies within the protein kinase domain of the Axl protein (PMID: 31825826). Y866F has been demonstrated to confer resistance to Egfr inhibitors in culture (PMID: 32439698), but demonstrates similar binding to Abl2 in the presence of ligand (PMID: 31825826), and does not induce cellular transformation in culture (PMID: 9671397), and therefore, is predicted to have no effect on Axl protein function. Y
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
AXL Y821F head and neck squamous cell carcinoma sensitive Cetuximab Preclinical - Cell line xenograft Actionable In a preclinical study, Erbitux (cetuximab) treatment inhibited proliferation of head and neck squamous cell carcinoma cells expressing AXL Y821F in culture, and delayed tumor growth in a cell line xenograft model (PMID: 32439698). 32439698
AXL over exp head and neck squamous cell carcinoma sensitive Bemcentinib + Cetuximab Preclinical - Cell culture Actionable In a preclinical study, Bemcentinib (BGB-324) treatment in combination with Erbitux (cetuximab) synergistically inhibited proliferation of head and neck squamous cell carcinoma cells overexpressing AXL in culture (PMID: 32439698). 32439698
AXL Y779F head and neck squamous cell carcinoma resistant Cetuximab Preclinical - Cell culture Actionable In a preclinical study, Erbitux (cetuximab) treatment did not inhibit proliferation of head and neck squamous cell carcinoma cells expressing AXL Y779F in culture PMID: 32439698). 32439698
AXL Y821F head and neck squamous cell carcinoma no benefit Bemcentinib + Cetuximab Preclinical - Cell culture Actionable In a preclinical study, combining Bemcentinib (BGB-324) with Erbitux (cetuximab) treatment inhibited proliferation of head and neck squamous cell carcinoma cells expressing AXL Y821F, but did not enhance inhibition compared to cells treated with Erbitux (cetuximab) alone in culture (PMID: 32439698). 32439698
AXL over exp head and neck squamous cell carcinoma resistant Cetuximab Preclinical - Cell line xenograft Actionable In a preclinical study, Erbitux (cetuximab) treatment did not decrease proliferation of head and neck squamous cell carcinoma cells overexpressing AXL in culture, and did not inhibit tumor growth in a cell line xenograft model (PMID: 32439698). 32439698
AXL over exp head and neck squamous cell carcinoma sensitive Cetuximab + Imatinib Preclinical - Cell line xenograft Actionable In a preclinical study, Gleevec (imatinib) treatment in combination with Erbitux (cetuximab) synergistically inhibited tumor growth and induced regression in an Erbitux (cetuximab)-resistant cell line xenograft model of head and neck squamous cell carcinoma overexpressing AXL (PMID: 32439698). 32439698
AXL Y866F head and neck squamous cell carcinoma resistant Cetuximab Preclinical - Cell culture Actionable In a preclinical study, Erbitux (cetuximab) treatment did not inhibit proliferation of head and neck squamous cell carcinoma cells expressing AXL Y866F in culture PMID: 32439698). 32439698