Superamento della resistenza adattativa alla bloccata di KRASG12D nel cancro pancreatic attraverso l'inibizione di percorso verticale.

PURPOSE: Oncogenic KRAS mutations are present in >90% of pancreatic ductal adenocarcinoma (PDAC), with KRASG12D being the most common. Mutant-selective KRASG12D inhibitors (KRASiG12D) have demonstrated promising initial clinical activity in KRASG12D-mutant PDAC. However, adaptive resistance to KRASi constrains efficacy in some tumor types, such as colorectal cancer, in which EGFR-mediated RAS-MAPK pathway reactivation can be targeted to improve response. Some studies have suggested a similar role for EGFR in PDAC, but the mechanisms of adaptive resistance to KRAS inhibition are unclear. EXPERIMENTAL DESIGN: Mechanisms of adaptive resistance to KRASiG12D were investigated in a panel of KRASG