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. (June 2016) A combinatorial strategy for treating KRAS-mutant lung cancer. Nature, 534. pp. 647-51. ISSN 1476-4687 (Electronic)0028-0836 (Linking)
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.
| Item Type: | Paper |
|---|---|
| Subjects: | bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > KRAS diseases & disorders > cancer > cancer types > lung cancer |
| CSHL Authors: | |
| Communities: | CSHL labs > Lowe lab School of Biological Sciences > Publications |
| Depositing User: | Matt Covey |
| Date: | 22 June 2016 |
| Date Deposited: | 29 Jun 2016 19:35 |
| Last Modified: | 22 Jul 2016 19:34 |
| PMCID: | PMC4939262 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/32920 |
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