Scientific publications

An integrative approach unveils FOSL1 as an oncogene vulnerability in KRAS-driven lung and pancreatic cancer

Feb 21, 2017 | Magazine: Nature Communications

Adrian Vallejo 1 , Naiara Perurena 1 , Elisabet Guruceaga 2 , Pawel K Mazur 3  4 , Susana Martinez-Canarias 1 , Carolina Zandueta 1 , Karmele Valencia 1 , Andrea Arricibita 1 , Dana Gwinn 4 , Leanne C Sayles 4 , Chen-Hua Chuang 4  5 , Laura Guembe 6 , Peter Bailey 7 , David K Chang 7  8  9  10  11 , Andrew Biankin 7  8  9  10  11 , Mariano Ponz-Sarvise 1  12 , Jesper B Andersen 13 , Purvesh Khatri 14  15 , Aline Bozec 16 , E Alejandro Sweet-Cordero 4 , Julien Sage 3  4 , Fernando Lecanda 1  17  18 , Silve Vicent 1  17  18


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.

CITATION  Nat Commun. 2017 Feb 21;8:14294.  doi: 10.1038/ncomms14294

Our authors

Adrián Vallejo Blanco
Project Graduate Solid Tumor Research Program
Susana Martínez Canarias
Laboratory technician Solid Tumor Research Program
Carolina Zandueta Pascual
Research Technician Solid Tumor Research Program
Dr. Karmele Valencia Leoz
Research Collaborator Solid Tumor Research Program