Team 3 (G. Favre): to determine how Rho GTPases control tumor progression
Our general aim is to understand the mechanisms involved in the deregulation of signaling pathways in cancerogenesis and their consequences in the response of antitumor therapy.
We focus primarily on RAS related GTPase RHOB that controls tumor progression of various cancers and emerged as an early DNA damage-inducible gene. However, very little is known about the mechanisms by whic RHOB exerts its different functions. To propose and validate new therapeutic strategies targeting Rho-dependant pathways, we develop basic, biotechnological, translational and clinical research.
We accumulated evidence that RHOB is a major player in oncology. We have shown that RHOB, by controlling PP2A activity, is important for DNA repair and the maintenance of genomic stability, and determines tumor aggressiveness in murine transgenic models. We identified RHOB as a new target to reverse the resistance to MAPK pathway inhibitors in lung cancer and melanoma. We also proposed RHOB as a biomarker to better predict the response to EGFR and MAPK inhibitors in lung cancer and melanoma, respectively.
To study specifically the role of active RHOB, we developed conformational sensors based on single chain antibodies and proposed a strategy to selectively knockdown active RHOB protein. We also developed a split-GFP biosensor in cells to monitor spatiotemporal RHOB activation and screen for RHO inhibitors.
We want now to identify the active RHOB-interacting proteins in the DNA damage response, and selectively inhibit RHOB activation in cellular and mouse models of lung cancer and melanoma. We have recently identified the RHO GTPase RND1 as an early damage-inducible gene, and C-JUN as a MAPK inhibitor-inducible gene.
We develop early phase clinical trials using combination of BRAF and AKT inhibitors in BRAFV600E mutated melanoma patients and EGFR and AKT inhibitors in EGFR mutated non-small cell lung cancer patients.
Together, we expect our approaches to bring new insights in the molecular signaling of oncogenic and stress genotoxic pathways and to develop new therapeutic strategies for lung cancer and melanoma.