From the understanding of KRAS-RAF membrane dynamics to new therapeutic strategies in cancer

ongoing

Cellular homeostasis is controlled by the RAS-MAPK pathway. This pathway is dysregulated in human diseases, especially cancer, in which more than 50% of cases carry aberrations that hyperactivate RAS-MAPK signaling. In this context, KRAS mutations are the most frequent oncogenic drivers. Therapeutic suppression of pathogenic KRAS-RAF-MAPK signaling to achieve disease control in cancer patients still represents a challenging target. KRAS dimers and multimers at the membrane (collectively referred, together with adaptors and effectors, as to “KRAS signalosome”) influence the activation of KRAS signaling. I provided the first biological evidence that dimerization is required for the function of oncogenic KRAS (Ambrogio et al, Cell, 2018). Indeed, one fascinating and still largely unexplored aspect of KRAS biology is the functional impact of KRAS complexes at the membrane for signaling and drug sensitivity. No inhibitors of oncogenic KRAS clustering have been identified so far. Interestingly, wild-type KRAS antagonizes oncogenic KRAS, resulting in reduced oncogenic signaling. The overarching goal of this proposal is the characterization in vitro and in vivo of the “KRAS signalosome” in terms of functional dynamics and related actionable vulnerabilities. My strong background in KRAS biology provides me with the expertise to propose an ambitious, yet feasible plan to understand the tumor suppressor effect of wild-type KRAS protomers in mutant KRAS-driven complexes by identifying and validating membrane interactors differentially recruited by wild-type and mutant KRAS (Work package 1). In parallel, I will study the relevance of RAF kinases localization at the membrane as key feature to sustain oncogenic MAPK activity in vivo (Work package 2). Finally, I will screen new compounds to interfere with RAFs function at the cell membrane and will determine the therapeutic impact of disrupting mutant KRAS signalosome using mouse models in vivo (Work package 3).