Cited by 1,134Melanoma and MAPK PathwaysLung Cancer Treatments and MutationsCancer Mechanisms and Therapy

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Widespread potential for growth-factor-driven resistance to anticancer kinase inhibitors

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Wilson, Timothy R., Fridlyand, Jane, Yan, Yibing, Penuel, Elicia, Burton, Luciana, Chan, Emily, Peng, Jing, Lin, Eva, Wang, Yulei, Sosman, Jeff, Ribas, Antoni, Li, Jiang, Moffat, John, Sutherlin, Daniel P., Koeppen, Hartmut, Merchant, Mark, Neve, Richard, Settleman, Jeff·2012·Nature

DOI 10.1038/nature11249PMC PMC3724525

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Abstract

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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Self-citation
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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: Wilson, Timothy R.
Penuel, Elicia
Chan, Emily
Peng, Jing
Lin, Eva
Wang, Yulei
Ribas, Antoni
Koeppen, Hartmut
Merchant, Mark
Neve, Richard
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2012-07
Volume: 487
Issue: 7408
Pages: 505-509
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/nature11249
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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