AXL Inhibition Sensitizes Mesenchymal Cancer Cells to Antimitotic Drugs
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Abstract
Molecularly targeted drug therapies have revolutionized cancer treatment; however, resistance remains a major limitation to their overall efficacy. Epithelial-to-mesenchymal transition (EMT) has been linked to acquired resistance to tyrosine kinase inhibitors (TKI), independent of mutational resistance mechanisms. AXL is a receptor tyrosine kinase associated with EMT that has been implicated in drug resistance and has emerged as a candidate therapeutic target. Across 643 human cancer cell lines that were analyzed, elevated AXL was strongly associated with a mesenchymal phenotype, particularly in triple-negative breast cancer and non–small cell lung cancer. In an unbiased screen of small-molecule inhibitors of cancer-relevant processes, we discovered that AXL inhibition was specifically synergistic with antimitotic agents in killing cancer cells that had undergone EMT and demonstrated associated TKI resistance. However, we did not find that AXL inhibition alone could overcome acquired resistance to EGFR TKIs in the EMT setting, as previously reported. These findings reveal a novel cotreatment strategy for tumors displaying mesenchymal features that otherwise render them treatment refractory. Cancer Res; 74(20); 5878–90. ©2014 AACR.
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AXL inhibition sensitizes drug-resistant mesenchymal tumor cells to anticancer agents, including antimitotic agents, EGFR inhibitors, and PI3K inhibitors.
“AXL inhibition has been reported to sensitize drug-resistant mesenchymal tumor cells to anticancer agents, including antimitotic agents, epidermal growth factor receptor (EGFR) inhibitors, and PI3K inhibitors”
From Hypoxic control of metastasis (2016) · cites this paper as [86]
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References 36 · Cited by 150
- Authors
- Wilson, C., Ye, X., Pham, T., Lin, E., Chan, S., McNamara, E., Neve, R. M., Belmont, L., Koeppen, H., Yauch, R. L., Ashkenazi, A., & Settleman, J.
- Affiliations
- Genentech (US)
- Corresponding author
- Settleman, Jeff
- ORCID
- Venue
- Cancer Research
- Published
- 2014-10-14
- Volume
- 74
- Issue
- 20
- Pages
- 5878-5890
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W2015023486
- Cited by
- 150
- References
- 36
- Citations by year
- 2026: 2 · 2025: 9 · 2024: 7 · 2023: 16 · 2022: 13 · 2021: 14 · 2020: 13 · 2019: 12 · 2018: 12 · 2017: 17 · 2016: 24 · 2015: 9 · 2014: 1
- FWCI
- 8.20
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Genentech
- Topics
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Health Sciences › Medicine › Pathology and Forensic Medicine › Cancer Mechanisms and Therapy
- Keywords
- AXL receptor tyrosine kinase, epithelial-mesenchymal transition, drug resistance, tyrosine kinase inhibitors, antimitotic agents, combination therapy, triple-negative breast cancer, non-small cell lung cancer, EGFR inhibitors, small molecule inhibitors
- MeSH terms
- Erlotinib Hydrochloride, Docetaxel, Axl Receptor Tyrosine Kinase, Animals, Antineoplastic Agents, Cisplatin, Drug Synergism, HeLa Cells, Humans, Mesoderm, Mice, Nude, Mitosis, Proto-Oncogene Proteins, Quinazolines, CDC2 Protein Kinase, Transforming Growth Factor beta, Cyclin-Dependent Kinases, Drug Resistance, Neoplasm, Receptor Protein-Tyrosine Kinases, Xenograft Model Antitumor Assays, Taxoids, Epithelial-Mesenchymal Transition
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