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


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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Figure 1: RTK ligands attenuate kinase inhibition in oncogene-addicted cancer cell lines.
Figure 2: Pro-survival pathway re-activation correlates with RTK-ligand rescue.
Figure 3: HGF promotes lapatinib resistance in HER2 -amplified breast cancer cell lines.
Figure 4: HGF promotes PLX4032 resistance in BRAF -mutant melanoma cell lines.


  1. Sharma, S. V. & Settleman, J. Oncogene addiction: setting the stage for molecularly targeted cancer therapy. Genes Dev. 21, 3214–3231 (2007)

    CAS  Article  PubMed  Google Scholar 

  2. Sequist, L. V. et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci. Transl. Med. 3, 75ra26 (2011)

    Article  PubMed  PubMed Central  Google Scholar 

  3. Garrett, J. T. & Arteaga, C. L. Resistance to HER2-directed antibodies and tyrosine kinase inhibitors: mechanisms and clinical implications. Cancer Biol. Ther. 11, 793–800 (2011)

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  4. Engelman, J. A. & Settleman, J. Acquired resistance to tyrosine kinase inhibitors during cancer therapy. Curr. Opin. Genet. Dev. 18, 73–79 (2008)

    CAS  Article  PubMed  Google Scholar 

  5. Moritz, A. et al. Akt–RSK–S6 kinase signaling networks activated by oncogenic receptor tyrosine kinases. Sci. Signal. 3, ra64 (2010)

    Article  PubMed  PubMed Central  Google Scholar 

  6. Zhang, W. & Huang, P. Cancer-stromal interactions: role in cell survival, metabolism and drug sensitivity. Cancer Biol. Ther. 11, 150–156 (2011)

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  7. McDermott, U. et al. Identification of genotype-correlated sensitivity to selective kinase inhibitors by using high-throughput tumor cell line profiling. Proc. Natl Acad. Sci. USA 104, 19936–19941 (2007)

    CAS  ADS  Article  PubMed  PubMed Central  Google Scholar 

  8. Wilson, T. R., Lee, D. Y., Berry, L., Shames, D. S. & Settleman, J. Neuregulin-1-mediated autocrine signaling underlies sensitivity to HER2 kinase inhibitors in a subset of human cancers. Cancer Cell 20, 158–172 (2011)

    CAS  Article  PubMed  Google Scholar 

  9. Yonesaka, K. et al. Autocrine production of amphiregulin predicts sensitivity to both gefitinib and cetuximab in EGFR wild-type cancers. Clin. Cancer Res. 14, 6963–6973 (2008)

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  10. Mueller, M. M. & Fusenig, N. E. Friends or foes — bipolar effects of the tumour stroma in cancer. Nature Rev. Cancer 4, 839–849 (2004)

    CAS  Article  Google Scholar 

  11. Grant, S., Qiao, L. & Dent, P. Roles of ERBB family receptor tyrosine kinases, and downstream signaling pathways, in the control of cell growth and survival. Front. Biosci. 7, d376–d389 (2002)

    CAS  Article  PubMed  Google Scholar 

  12. Kwak, E. L. et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N. Engl. J. Med. 363, 1693–1703 (2010)

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  13. Chapman, P. B. et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N. Engl. J. Med. 364, 2507–2516 (2011)

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  14. Straussman, R. et al. Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion. Nature (2012)

  15. Gilbert, L. A. & Hemann, M. T. DNA damage-mediated induction of a chemoresistant niche. Cell 143, 355–366 (2010)

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  16. Liang, K. et al. Recombinant human erythropoietin antagonizes trastuzumab treatment of breast cancer cells via Jak2-mediated Src activation and PTEN inactivation. Cancer Cell 18, 423–435 (2010)

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  17. Quintana, E. et al. Phenotypic heterogeneity among tumorigenic melanoma cells from patients that is reversible and not hierarchically organized. Cancer Cell 18, 510–523 (2010)

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  18. Calbo, J. et al. A functional role for tumor cell heterogeneity in a mouse model of small cell lung cancer. Cancer Cell 19, 244–256 (2011)

    CAS  Article  PubMed  Google Scholar 

  19. Sharma, S. V. et al. A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations. Cell 141, 69–80 (2010)

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  20. Turke, A. B. et al. Preexistence and clonal selection of MET amplification in EGFR mutant NSCLC. Cancer Cell 17, 77–88 (2010)

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  21. Stommel, J. M. et al. Coactivation of receptor tyrosine kinases affects the response of tumor cells to targeted therapies. Science 318, 287–290 (2007)

    CAS  ADS  Article  PubMed  Google Scholar 

  22. Nazarian, R. et al. Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation. Nature 468, 973–977 (2010)

    CAS  ADS  Article  PubMed  PubMed Central  Google Scholar 

  23. Guix, M. et al. Acquired resistance to EGFR tyrosine kinase inhibitors in cancer cells is mediated by loss of IGF-binding proteins. J. Clin. Invest. 118, 2609–2619 (2008)

    CAS  PubMed  PubMed Central  Google Scholar 

  24. McDermott, U., Pusapati, R. V., Christensen, J. G., Gray, N. S. & Settleman, J. Acquired resistance of non-small cell lung cancer cells to MET kinase inhibition is mediated by a switch to epidermal growth factor receptor dependency. Cancer Res. 70, 1625–1634 (2010)

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  25. Johannessen, C. M. et al. COT drives resistance to RAF inhibition through MAP kinase pathway reactivation. Nature 468, 968–972 (2010)

    CAS  ADS  Article  PubMed  PubMed Central  Google Scholar 

  26. Liu, L. et al. Novel mechanism of lapatinib resistance in HER2-positive breast tumor cells: activation of AXL. Cancer Res. 69, 6871–6878 (2009)

    CAS  Article  PubMed  Google Scholar 

  27. Engelman, J. A. et al. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science 316, 1039–1043 (2007)

    CAS  ADS  Article  PubMed  Google Scholar 

  28. Liederer, B. M. et al. Preclinical absorption, distribution, metabolism, excretion, and pharmacokinetic-pharmacodynamic modelling of N-(4-(3-((3S,4R)-1-ethyl-3-fluoropiperidine-4-ylamino)-1H-pyrazolo[3,4-b]p yridin-4-yloxy)-3-fluorophenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyrida zine-4-carboxamide, a novel MET kinase inhibitor. Xenobiotica 41, 327–339 (2011)

    CAS  Article  PubMed  Google Scholar 

  29. Catenacci, D. V. T. et al. Durable complete response of metastatic gastric cancer with anti-met therapy followed by resistance at recurrence. Cancer Discovery 1, 573–579 (2011)

    Article  PubMed  PubMed Central  Google Scholar 

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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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Authors and Affiliations



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.

Corresponding author

Correspondence to Jeff Settleman.

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Competing interests

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).

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