We proudly announce that it is publiched the research of KINETO Lab and collaborators on targeting KRAS with combination of KRAS-G12C and Farnesyl-transferase inhibitors, in British Journal of Cancer. Our findings warrant the clinical exploration of KRAS-G12C inhibitors in combination with farnesyl-transferase inhibitors.

De novo and acquired resistance limit the efficacy of approved KRAS-G12C inhibitors for the treatment of KRAS-G12C mutant lung cancer. However, several combinations are in clinical development. Our study shows the potential of combining G12C inhibitors with farnesyl-transferase inhibitors on human lung, colorectal and pancreatic adenocarcinoma cells in vitro in 2D, 3D and in subcutaneous xenograft models of lung adenocarcinoma.

Combination of tipifarnib with sotorasib shows synergistic inhibitory effects on lung adenocarcinoma cells in vitro in 2D and 3D. Mechanistically, we present antiproliferative effect of the combination and interference with compensatory HRAS activation and RHEB and lamin farnesylation. Enhanced efficacy of sotorasib in combination with tipifarnib is recapitulated in the subcutaneous xenograft model of lung adenocarcinoma. Finally, combination of additional KRAS-G12C and farnesyl-transferase inhibitors also shows synergism in lung, colorectal and pancreatic adenocarcinoma cellular models.

The publication can be accessed under the following link.