@article{d838559bdbf24271be60bfc12dbd5256,
title = "A combinatorial strategy for treating KRAS-mutant lung cancer",
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.",
author = "Eusebio Manchado and Susann Weissmueller and Morris, {John P.} and Chen, {Chi Chao} and Ramona Wullenkord and Amaia Lujambio and {De Stanchina}, Elisa and Poirier, {John T.} and Gainor, {Justin F.} and Corcoran, {Ryan B.} and Engelman, {Jeffrey A.} and Rudin, {Charles M.} and Neal Rosen and Lowe, {Scott W.}",
note = "Funding Information: Acknowledgements We thank M. S{\'a}nchez-C{\'e}spedes, 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. Publisher Copyright: {\textcopyright} 2016 Macmillan Publishers Limited. All rights reserved.",
year = "2016",
doi = "10.1038/nature18600",
language = "English",
volume = "534",
pages = "647--651",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",
number = "7609",
}