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

Research output: Contribution to journalJournal articleResearchpeer-review

  • Adrian Vallejo
  • Naiara Perurena
  • Elisabet Guruceaga
  • Pawel K Mazur
  • Susana Martinez-Canarias
  • Carolina Zandueta
  • Karmele Valencia
  • Andrea Arricibita
  • Dana Gwinn
  • Leanne C Sayles
  • Chen-Hua Chuang
  • Laura Guembe
  • Peter Bailey
  • David K Chang
  • Andrew Biankin
  • Mariano Ponz-Sarvise
  • Purvesh Khatri
  • Aline Bozec
  • E Alejandro Sweet-Cordero
  • Julien Sage
  • Fernando Lecanda
  • Silve Vicent

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.

Original languageEnglish
Article number14294
JournalNature Communications
Volume8
Number of pages14
ISSN2041-1723
DOIs
Publication statusPublished - 2017

    Research areas

  • Journal Article

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