TY - JOUR
T1 - An integrative approach unveils FOSL1 as an oncogene vulnerability in KRAS-driven lung and pancreatic cancer
AU - Vallejo, Adrian
AU - Perurena, Naiara
AU - Guruceaga, Elisabet
AU - Mazur, Pawel K.
AU - Martinez-Canarias, Susana
AU - Zandueta, Carolina
AU - Valencia, Karmele
AU - Arricibita, Andrea
AU - Gwinn, Dana
AU - Sayles, Leanne C.
AU - Chuang, Chen Hua
AU - Guembe, Laura
AU - Bailey, Peter
AU - Chang, David K.
AU - Biankin, Andrew
AU - Ponz-Sarvise, Mariano
AU - Andersen, Jesper B.
AU - Khatri, Purvesh
AU - Bozec, Aline
AU - Sweet-Cordero, E. Alejandro
AU - Sage, Julien
AU - Lecanda, Fernando
AU - Vicent, Silve
N1 - Publisher Copyright:
© 2017 The Author(s).
PY - 2017/2/21
Y1 - 2017/2/21
N2 - 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.
AB - 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.
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U2 - 10.1038/ncomms14294
DO - 10.1038/ncomms14294
M3 - Article
C2 - 28220783
AN - SCOPUS:85013453512
SN - 2041-1723
VL - 8
JO - Nature communications
JF - Nature communications
M1 - 14294
ER -