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Widespread potential for growth-factor-driven resistance to anticancer kinase inhibitors
Open accessAbstract
Mutationally activated kinases define a clinically validated class of targets for cancer drug therapy. However, the efficacy of kinase inhibitors in patients whose tumours harbour such alleles is invariably limited by innate or acquired drug resistance. The identification of resistance mechanisms has revealed a recurrent theme—the engagement of survival signals redundant to those transduced by the targeted kinase. Cancer cells typically express multiple receptor tyrosine kinases (RTKs) that mediate signals that converge on common critical downstream cell-survival effectors—most notably, phosphatidylinositol-3-OH kinase (PI(3)K) and mitogen-activated protein kinase (MAPK). Consequently, an increase in RTK-ligand levels, through autocrine tumour-cell production, paracrine contribution from tumour stroma or systemic production, could confer resistance to inhibitors of an oncogenic kinase with a similar signalling output. Here, using a panel of kinase-'addicted' human cancer cell lines, we found that most cells can be rescued from drug sensitivity by simply exposing them to one or more RTK ligands. Among the findings with clinical implications was the observation that hepatocyte growth factor (HGF) confers resistance to the BRAF inhibitor PLX4032 (vemurafenib) in BRAF-mutant melanoma cells. These observations highlight the extensive redundancy of RTK-transduced signalling in cancer cells and the potentially broad role of widely expressed RTK ligands in innate and acquired resistance to drugs targeting oncogenic kinases.
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“For example HGF has been found to confer resistance to the BRAF inhibitor vemurafenib in BRAF-mutant melanoma cells (Wilson et al., 2012).”
From ERBB Receptors: From Oncogene Discovery to Basic Science to Mechanism-Based Cancer Therapeutics (2014) · cites this paper as Wilson et al., 2012
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Metadata
- Authors
- Wilson, T. R., Fridlyand, J., Yan, Y., Penuel, E., Burton, L., Chan, E., Peng, J., Lin, E., Wang, Y., Sosman, J., Ribas, A., Li, J., Moffat, J., Sutherlin, D. P., Koeppen, H., Merchant, M., Neve, R., & Settleman, J.
- Affiliations
- Genentech (US)
- Vanderbilt University Medical Center (US)
- University of California, Los Angeles (US)
- Corresponding author
- Settleman, Jeff
- ORCID
- Venue
- Nature
- Published
- 2012-07
- Volume
- 487
- Issue
- 7408
- Pages
- 505-509
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3724525
- OpenAlex
- W1999025555
- Cited by
- 1,134
- References
- 29
- Citations by year
- 2026: 23 · 2025: 16 · 2024: 31 · 2023: 46 · 2022: 47 · 2021: 51 · 2020: 65 · 2019: 70 · 2018: 85 · 2017: 87 · 2016: 125 · 2015: 137 · 2014: 166 · 2013: 150 · 2012: 34
- FWCI
- 62.91
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Cancer Institute (K24CA097588)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Mechanisms and Therapy
- Keywords
- drug resistance, kinase inhibitors, receptor tyrosine kinase, growth factors, hepatocyte growth factor, BRAF inhibitors, vemurafenib, melanoma, tumor microenvironment, phosphatidylinositol 3-kinase, mitogen-activated protein kinase, combination therapy
- MeSH terms
- Lapatinib, Vemurafenib, Antineoplastic Agents, Breast Neoplasms, Cell Survival, Female, Humans, Indoles, Ligands, Melanoma, Quinazolines, Sulfonamides, Signal Transduction, Hepatocyte Growth Factor, Erb-b2 Receptor Tyrosine Kinases, Receptor, ErbB-2, Drug Resistance, Neoplasm, Phosphatidylinositol 3-Kinases, Receptor Protein-Tyrosine Kinases, Mitogen-Activated Protein Kinases, Cell Line, Tumor, Protein Kinase Inhibitors, Proto-Oncogene Proteins B-raf
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