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AXL mediates resistance to cetuximab therapy.
- Source :
-
Cancer research [Cancer Res] 2014 Sep 15; Vol. 74 (18), pp. 5152-64. Date of Electronic Publication: 2014 Aug 18. - Publication Year :
- 2014
-
Abstract
- 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 (Ctx(R) cells). Using RNAi methods and novel AXL-targeting agents, we found that AXL activation stimulated cell proliferation, EGFR activation, and MAPK signaling in Ctx(R) cells. Notably, EGFR directly regulated the expression of AXL mRNA through MAPK signaling and the transcription factor c-Jun in Ctx(R) cells, creating a positive feedback loop that maintained EGFR activation by AXL. Cetuximab-sensitive parental cells were rendered resistant to cetuximab by stable overexpression 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. Cancer Res; 74(18); 5152-64. ©2014 AACR.<br /> (©2014 American Association for Cancer Research.)
- Subjects :
- Animals
Carcinoma, Non-Small-Cell Lung genetics
Carcinoma, Non-Small-Cell Lung pathology
Carcinoma, Squamous Cell genetics
Carcinoma, Squamous Cell pathology
Cell Growth Processes drug effects
Cell Line, Tumor
Cetuximab
Drug Resistance, Neoplasm
Head and Neck Neoplasms genetics
Head and Neck Neoplasms pathology
Humans
Lung Neoplasms pathology
Mice
Mice, Nude
Proto-Oncogene Proteins genetics
Proto-Oncogene Proteins metabolism
RNA, Small Interfering administration & dosage
RNA, Small Interfering genetics
Receptor Protein-Tyrosine Kinases genetics
Receptor Protein-Tyrosine Kinases metabolism
Squamous Cell Carcinoma of Head and Neck
Transfection
Xenograft Model Antitumor Assays
Axl Receptor Tyrosine Kinase
Antibodies, Monoclonal, Humanized pharmacology
Antineoplastic Agents pharmacology
Carcinoma, Non-Small-Cell Lung drug therapy
Carcinoma, Non-Small-Cell Lung enzymology
Carcinoma, Squamous Cell drug therapy
Carcinoma, Squamous Cell enzymology
Head and Neck Neoplasms drug therapy
Head and Neck Neoplasms enzymology
Proto-Oncogene Proteins biosynthesis
Receptor Protein-Tyrosine Kinases biosynthesis
Subjects
Details
- Language :
- English
- ISSN :
- 1538-7445
- Volume :
- 74
- Issue :
- 18
- Database :
- MEDLINE
- Journal :
- Cancer research
- Publication Type :
- Academic Journal
- Accession number :
- 25136066
- Full Text :
- https://doi.org/10.1158/0008-5472.CAN-14-0294