How do KRAS-mutant tumors survive targeted therapy? Dr. Simon Bayle @MoffittNews's presentation at #AACR26 shows KRAS blockade drives cancer cells into a drug tolerant persister (DTP) state -cells that are slow-cycling, activate autophagy, and ready to bounce back when treatment stops.
The DTPs under metabolic rewiring (oxidative phosphorylation, glycolysis, increased MYC targets) mirroring DTP states seen across other cancer models. Does blocking autophagy reverse the DTP state? MR-2088, a novel ULK1/2 inhibitor inhibits ATG13 phosphorylation and synergizes with sotorasib to shrink KRAS G12C #NSCLC tumors in mouse models.
· Autophagy may be a key survival mechanism fueling KRAS inhibitor resistance
· ULK1/2 inhibition is an emerging strategy to shut it down
@KRASKickers #lcsm