Ali Smith
Senior Scientist Kura Oncology
Seminars
Tuesday 16th September 2025
Farnesyl Transferase Inhibition Restores RAS Inhibitor Sensitivity in Tumors Exhibiting Innate or Adaptive Resistance
11:00 am
- Persistent mTORC1 activity is a frequent, nongenetic driver of inherent and adaptive resistance to RAS inhibition in KRAS-mutant preclinical models. This vulnerability is targetable with the farnesyl transferase inhibitor KO-2806, which blocks mTORC1 activation via RHEB, while sparing mTORC2 and its associated toxicities
- Across a panel of NSCLC and CRC xenograft models, KO-2806 improves tumor growth inhibition or deepens regressions induced by mutant-selective or pan-RAS inhibitors. Enhanced antitumor activity corresponds with stronger inhibition of mTORC1 signaling
- Xenograft tumors relapsing in vivo can be re-sensitized to RAS inhibition via addition of KO-2806, an effect not achievable by switching RAS inhibitor class. Farnesyl transferase inhibitors have potential as versatile RAS companion agents given their activity across tumor types, RAS inhibitor classes, and prior-treatment settings
