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

Wilson TR, 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 DP, Koeppen H, Merchant M, Neve R, Settleman J
Nature. 2012 487 (7408): 505-9

PMID: 22763448 · PMCID: PMC3724525 · DOI:10.1038/nature11249

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.

MeSH Terms (22)

Antineoplastic Agents Breast Neoplasms Cell Line, Tumor Cell Survival Drug Resistance, Neoplasm Female Hepatocyte Growth Factor Humans Indoles Lapatinib Ligands Melanoma Mitogen-Activated Protein Kinases Phosphatidylinositol 3-Kinases Protein Kinase Inhibitors Proto-Oncogene Proteins B-raf Quinazolines Receptor, ErbB-2 Receptor Protein-Tyrosine Kinases Signal Transduction Sulfonamides Vemurafenib

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