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

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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

851 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)505-509
Number of pages5
JournalNature
Volume487
Issue number7408
DOIs
StatePublished - Jul 26 2012

ASJC Scopus subject areas

  • General

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