AXL mediates resistance to cetuximab therapy

Toni M. Brand, Mari Iida, Andrew P. Stein, Kelsey L. Corrigan, Cara M. Braverman, Neha Luthar, Mahmoud Toulany, Parkash S. Gill, Ravi Salgia, Randall J. Kimple, Deric L. Wheeler*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

126 Scopus citations


The EGFR antibody cetuximab is used to treat numerous cancers, but intrinsic and acquired resistance to this agent is a common clinical outcome. In this study, we show that overexpression of the oncogenic receptor tyrosine kinase AXL is sufficient to mediate acquired resistance to cetuximab in models of non-small cell lung cancer (NSCLC) and head and neck squamous cell carcinoma (HNSCC), where AXL was overexpressed, activated, and tightly associated with EGFR expression in cells resistant to cetuximab (CtxR cells). Using RNAi methods and novel AXL-targeting agents, we found that AXL activation stimulated cell proliferation, EGFR activation, and MAPK signaling in CtxR cells. Notably, EGFR directly regulated the expression of AXL mRNA through MA signaling and the transcription factor c-Jun in CtxR cells, creating a positive feedback loop that maintained EGFR activation by AXL. Cetuximab-sensitive parental cells were rendered resistant to cetuximab by stable over-expression of AXL or stimulation with EGFR ligands, the latter of which increased AXL activity and association with the EGFR. In tumor xenograft models, the development of resistance following prolonged treatment with cetuximab was associated with AXL hyperactivation and EGFR association. Furthermore, in an examination of patient-derived xenografts established from surgically resected HNSCCs, AXL was overexpressed and activated in tumors that displayed intrinsic resistance to cetuximab. Collectively, our results identify AXL as a key mediator of cetuximab resistance, providing a rationale for clinical evaluation of AXL-targeting drugs to treat cetuximab-resistant cancers.

Original languageEnglish (US)
Pages (from-to)5152-5164
Number of pages13
JournalCancer Research
Issue number18
StatePublished - Aug 18 2014
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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