A combinatorial strategy for treating KRAS-mutant lung cancer Journal Article

Authors: Manchado, E.; Weissmueller, S.; Morris, J. P.; Chen, C. C.; Wullenkord, R.; Lujambio, A.; de Stanchina, E.; Poirier, J. T.; Gainor, J. F.; Corcoran, R. B.; Engelman, J. A.; Rudin, C. M.; Rosen, N.; Lowe, S. W.
Article 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.
Keywords: receptor tyrosine kinase; ras; colon-cancer; models; acquired-resistance; potent; selective inhibitor; mek inhibition; mediated reactivation; feedback activation
Journal Title: Nature
Volume: 534
Issue: 7609
ISSN: 0028-0836
Publisher: Nature Publishing Group  
Date Published: 2016-06-22
Start Page: 647
End Page: 651
Language: English
ACCESSION: WOS:000378676000028
DOI: 10.1038/nature18600
PMCID: PMC4939262
PUBMED: 27338794
Notes: Article -- Source: Wos
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