Inhibition of mutant KRAS challenged cancer research for decades. Recently, allele-specific
inhibitors were approved for the treatment of KRAS-G12C mutant lung cancer. However,
de novo and acquired resistance limit their efficacy and several combinations are
in clinical development. Our study shows the potential of combining G12C inhibitors
with farnesyl-transferase inhibitors.Combinations of clinically approved farnesyl-transferase
inhibitors and KRAS G12C inhibitors are tested on human lung, colorectal and pancreatic
adenocarcinoma cells in vitro in 2D, 3D and subcutaneous xenograft models of lung
adenocarcinoma. Treatment effects on migration, proliferation, apoptosis, farnesylation
and RAS signaling were measured by histopathological analyses, videomicroscopy, cell
cycle analyses, immunoblot, immunofluorescence and RAS pulldown.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 G1C and farnesyl-transferase inhibitors also shows synergism in lung, colorectal
and pancreatic adenocarcinoma cellular models.Our findings warrant the clinical exploration
of KRAS-G12C inhibitors in combination with farnesyl-transferase inhibitors.
