Research Projects

Regulation of cell and non-cell autonomous mechanisms by novel synthetic-lethal interactions with KRAS

Silvestre Vicent Cambra
Research program
Solid Tumors
Disease
Lung cancer

Project information

KRAS represents the most frequently mutated oncogene in several solid tumors including lung adenocarcinoma (LUAD) where it associates with poor prognosis due to the lack of curative options. Previously we have described, through a multimodal strategy integrating cross-species transcriptome analyses and a bioinformatics approach of clinical data from multiple tumor types driven by mutant KRAS, a critically convergent and necessary gene signature for tumor homeostasis (Vallejo et al., Nature Communications, 2017). Subsequent functional and mechanistic dissection identified a member of this signature, FOSL1, as avulnerability in LUAD and other incurable solid tumors, demonstrating the robustness of our computational-clinical-functional strategy.

This gene signature includes additional genes which are overexpresed in oncogenic KRAS tumors with potential clinical and functional relevance. In preliminary results we have determined the dependence on the expression of mutant KRAS of a new member of this signature and found that high expression levels of this gene associate with dismal prognosis in LUAD patients. We postulate that this gene constitutes a key element induced by oncogenic KRAS whose mechanism of action involves tumor cell and non-cell autonomous functions. In this project we will focus on understanding part of its mechanism of action in the context of KRAS oncogenesis in LUAD. 

This project will contribute to define the role of a new KRAS effector and its regulated events in LUAD. Future studies will be aimed to assess potential inhibitory compounds against this protein or its mediators in preclinical models.

  • Reference: MINECO (SAF2017-89944-R)
  • Duration: 3 years
  • Start date: January 1, 2018
  • End date: December 31, 2020
  • Funder: MINECO
  • Grant: 140.000 €
  • Nature of project: International

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