Abstract

Therapeutic targeting of KRAS-mutant lung adenocarcinoma represents a major goal of clinical oncology. KRAS itself has proved difficult to inhibit, and the effectiveness of agents that target key KRAS effectors has been thwarted by activation of compensatory or parallel pathways that limit their efficacy as single agents. Here we take a systematic approach towards identifying combination targets for trametinib, a MEK inhibitor approved by the US Food and Drug Administration, which acts downstream of KRAS to suppress signalling through the mitogen-activated protein kinase (MAPK) cascade. Informed by a short-hairpin RNA screen, we show that trametinib provokes a compensatory response involving the fibroblast growth factor receptor 1 (FGFR1) that leads to signalling rebound and adaptive drug resistance. As a consequence, genetic or pharmacological inhibition of FGFR1 in combination with trametinib enhances tumour cell death in vitro and in vivo. This compensatory response shows distinct specificities: it is dominated by FGFR1 in KRAS-mutant lung and pancreatic cancer cells, but is not activated or involves other mechanisms in KRAS wild-type lung and KRAS-mutant colon cancer cells. Importantly, KRAS-mutant lung cancer cells and patients’ tumours treated with trametinib show an increase in FRS2 phosphorylation, a biomarker of FGFR activation; this increase is abolished by FGFR1 inhibition and correlates with sensitivity to trametinib and FGFR inhibitor combinations. These results demonstrate that FGFR1 can mediate adaptive resistance to trametinib and validate a combinatorial approach for treating KRAS-mutant lung cancer.

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Acknowledgements

We thank M. Sánchez-Céspedes, R. Somwar, and H. Varmus for sharing cell lines; S. Tian, J. Ahn, M. Taylor, A. Shroff, and J. Plevy for technical assistance; C. J. Sherr, L. E. Dow, P. Lito, T. Kastenhuber, and J. Leibold for advice on experimental design and/or for editing the manuscript; and other members of the Lowe laboratory for advice and discussions. This work was supported by a program project grant from the National Cancer Institute (S.W.L., N.R.), a grant from the Center of Experimental Therapeutics (S.W.L., N.R.), a Stand Up To Cancer grant from the American Association for Cancer Research (N.R., J.A.E., C.R.), and a Cancer Center Support grant to MSKCC. E.M. was supported by The Jane Coffin Childs Memorial Fund for Medical Research and a K99/R00 grant from the National Institutes of Health/National Cancer Institute. S.W. was supported by the Annette Kade Fellowship from the Watson School of Biological Sciences. R.W. was supported by a Carl-Duisberg Fellowship from the Bayer Foundation. A.L. was supported by an EMBO Long-Term fellowship. E.d.S. received support through the Geoffrey Beene Cancer Research Center. S.W.L. is the Geoffrey Beene Chair of Cancer Biology and a Howard Hughes Medical Institute investigator.

Author information

Author notes

    • Amaia Lujambio

    Present address: Department of Oncological Sciences, Liver Cancer Program, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA

Affiliations

  1. Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA

    • Eusebio Manchado
    • , Susann Weissmueller
    • , John P. Morris
    • , Chi-Chao Chen
    • , Ramona Wullenkord
    • , Amaia Lujambio
    •  & Scott W. Lowe
  2. Watson School of Biological Sciences, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA

    • Susann Weissmueller
  3. Weill Cornell Graduate School of Medical Sciences, Cornell University, New York, New York 10065, USA

    • Chi-Chao Chen
  4. Department of Molecular Pharmacology and Chemistry, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA

    • Elisa de Stanchina
    • , John T. Poirier
    • , Charles M. Rudin
    •  & Neal Rosen
  5. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA

    • John T. Poirier
    • , Charles M. Rudin
    •  & Neal Rosen
  6. Massachusetts General Hospital Cancer Center, Department of Medicine and Harvard Medical School, Boston, MA 02114, USA

    • Justin F. Gainor
    • , Ryan B. Corcoran
    •  & Jeffrey A. Engelman
  7. Howard Hughes Medical Institute, New York, New York 10065, USA

    • Scott W. Lowe

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Contributions

E.M. conceived the project, performed and analysed experiments, and wrote the paper with assistance of all authors. S.W., C.C., and R.W. performed and analysed in vitro experiments. S.W., J.P.M., and E.d.S. performed and analysed in vivo experiments. A.L. helped design and produce the shRNA library. J.T.P. and C.R. provided and analysed patient-derived xenografts. J.F.G., R.B.C., and J.A.E. provided human specimens. N.R. conceived the project, supervised experiments, and wrote the paper. S.W.L. conceived the project, supervised experiments, analysed data, and wrote the paper.

Competing interests

N.R. is a member of the scientific advisory board of Novartis, AstraZeneca, and Chugai Pharmaceutical.

Corresponding authors

Correspondence to Neal Rosen or Scott W. Lowe.

Reviewer Information

Nature thanks J. Tyner and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Extended data

Supplementary information

Excel files

  1. 1.

    Supplementary Table 1

    This table contains primary screening data. Primary data for Figure 1a and Extended Data Figure 1f, g, h. shRNA screen under doxycycline or doxycycline and trametinib 25 nM.

  2. 2.

    Supplementary Table 2

    This file contains additional shRNA sequences. shRNA sequences for Figure 2f and Extended Data Figure 4h, i.

PDF files

  1. 1.

    Supplementary Figure

    This file contains full scanned blot images with size markers.

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DOI

https://doi.org/10.1038/nature18600

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