An integrative approach unveils FOSL1 as an oncogene vulnerability in KRAS-driven lung and pancreatic cancer
Vallejo A, Perurena N, Guruceaga E, Mazur PK, Martinez-Canarias S, Zandueta C, Valencia K, Arricibita A, Gwinn D, Sayles LC, Chuang CH, Guembe L, Bailey P, Chang DK, Biankin A, Ponz-Sarvise M, Andersen JB, Khatri P, Bozec A, Sweet-Cordero EA, Sage J, Lecanda F, Vicent S (2017)
Publication Type: Journal article
Publication year: 2017
Journal
Book Volume: 8
Pages Range: 14294
DOI: 10.1038/ncomms14294
Abstract
KRAS mutated tumours represent a large fraction of human cancers, but the vast majority remains refractory to current clinical therapies. Thus, a deeper understanding of the molecular mechanisms triggered by KRAS oncogene may yield alternative therapeutic strategies. Here we report the identification of a common transcriptional signature across mutant KRAS cancers of distinct tissue origin that includes the transcription factor FOSL1. High FOSL1 expression identifies mutant KRAS lung and pancreatic cancer patients with the worst survival outcome. Furthermore, FOSL1 genetic inhibition is detrimental to both KRAS-driven tumour types. Mechanistically, FOSL1 links the KRAS oncogene to components of the mitotic machinery, a pathway previously postulated to function orthogonally to oncogenic KRAS. FOSL1 targets include AURKA, whose inhibition impairs viability of mutant KRAS cells. Lastly, combination of AURKA and MEK inhibitors induces a deleterious effect on mutant KRAS cells. Our findings unveil KRAS downstream effectors that provide opportunities to treat KRAS-driven cancers.
Authors with CRIS profile
Involved external institutions
Universidad de Navarra
Spain (ES)
Bankstown-Lidcombe Hospital
Australia (AU)
Stanford University
United States (USA) (US)
University of Glasgow
United Kingdom (GB)
University of Copenhagen
Denmark (DK)
Spain (ES)
Bankstown-Lidcombe Hospital
Australia (AU)
Stanford University
United States (USA) (US)
University of Glasgow
United Kingdom (GB)
University of Copenhagen
Denmark (DK)
How to cite
APA:
Vallejo, A., Perurena, N., Guruceaga, E., Mazur, P.K., Martinez-Canarias, S., Zandueta, C.,... Vicent, S. (2017). An integrative approach unveils FOSL1 as an oncogene vulnerability in KRAS-driven lung and pancreatic cancer. Nature Communications, 8, 14294. https://dx.doi.org/10.1038/ncomms14294
MLA:
Vallejo, Adrian, et al. "An integrative approach unveils FOSL1 as an oncogene vulnerability in KRAS-driven lung and pancreatic cancer." Nature Communications 8 (2017): 14294.
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