At AACR Annual Meeting which held in San Diego Convention Center, San Diego, California, USA, from April 5^th to 10^th, 2024, our chief scientific officer Dr. József Tóvári presented the poster with the title „Antitumor effects of KRAS-G12C inhibitors can be improved by farnesyltransferase inhibitors in preclinical models”. Our findings suggest the potential clinical applicability of the combination of KRAS-G12C inhibitors and farnesyl-transferase inhibitors.

It was observed that farnesyltransferase inhibitors (FTI) failed as monotherapies for various cancer types until the discovery of their potency in HRAS mutant human head and neck and bladder cancers. On the other hand, RAS mutant cancers have been a great challenge for cancer research until the discoveries and approvals of several KRAS-G12C allele specific inhibitors. However, G12C inhibitors were effective mainly in lung cancer and, de novo and acquired resistance limited their efficacy prompting the development of various combinational modalities including immunotherapy as well as SOS- and SHP2-inhibitors.

In this study, clinically approved farnesyl-transferase inhibitors (tipifarnib and lonafarnib) were combined with, novel KRAS G12C inhibitors (sotorasib and adagrasib) using on human lung-, pancreatic and colorectal- adenocarcinoma cells in vitro and in vivo. Antitumoral effects were evaluated for proliferation, apoptosis and migratory activity. Mechanisms of action were investigated by immunoblot analyzes of various farnesylated protein, RAS activation and signaling, videomicroscopy and also histopathological analyzes of xenograft tumors.

Results revealed synergistic anticancer effects upon the combination of FTIs with G12C inhibitors in KRAS G12C mutant human cancer cell lines in vitro. We found that the combination interfered with the compensatory re-activation of HRAS, farnesylation of RHEB in the PI3K/mTOR pathway and lamin structure. Furthermore, we observed enhanced efficacy of sotorasib upon combination with tipifarnib in the xenograft models of lung adenocarcinoma affecting mitotic and apoptotic rates and inducing necrosis.

Our findings suggest the potential clinical applicability of the combination of KRAS-G12C inhibitors and farnesyl-transferase inhibitors. Furthermore, our preliminary data suggest that the synergistic effect of FTIs on G12C inhibitors can be projected to KRAS-G12D inhibitors as well.

The poster number is LB220/15, and it was presented at the section LBPO.TB01 – Late-Breaking Research: Tumor Biology 1, on April 8^th, 2024, 1:30 PM – 5:00 PM.

The poster can be downloaded here, while about the poster at AACR conference you can find here.