Abstract
Mutationally activated kinases define a clinically validated class of targets for cancer drug therapy1. However, the efficacy of kinase inhibitors in patients whose tumours harbour such alleles is invariably limited by innate or acquired drug resistance2,3. The identification of resistance mechanisms has revealed a recurrent theme—the engagement of survival signals redundant to those transduced by the targeted kinase4. 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)5. Consequently, an increase in RTK-ligand levels, through autocrine tumour-cell production, paracrine contribution from tumour stroma6 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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Acknowledgements
We thank members of the Settleman laboratory, G. Bray and C. Bowdoin for helpful discussions, K. Trunzer and B. Nelson for assistance with access to clinical samples.
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T.R.W. and J.S. designed the study, analysed data, discussed results and co-wrote the paper. T.R.W. performed in vitro experiments. T.R.W., E.L. and R.N. designed and performed the 446 soluble factor screen. H.K. performed immunohistochemistry analysis. E.C., J.P. and M.M. designed and performed in vivo experiments. E.P., L.B., Y.W. and Y.Y. assessed BRIM2 study material, including HGF enzyme-linked immunosorbent assay (ELISA) from plasma. J.F. carried out the biostatistical analysis. J.L. carried out efficacy and safety analyses on the BRIM2 study. J.S. and A.R. were clinical investigators on the BRIM2 study. J.M. and D.P.S. characterized GDC-0712.
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T.R.W., J.F., Y.Y., E.P., L.B., E.C., J.P., E.L., Y.W., H.K., M.M., R.N., J.M., D.P.S. and J.S. are employees of Genentech, Inc., a member of the Roche group, and may have equity interest in Roche. J.L. is an employee of the Roche group and may have equity interest in Roche.
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Wilson, T., Fridlyand, J., Yan, Y. et al. Widespread potential for growth-factor-driven resistance to anticancer kinase inhibitors. Nature 487, 505–509 (2012). https://doi.org/10.1038/nature11249
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DOI: https://doi.org/10.1038/nature11249
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