Overcoming adaptive resistance to KRASG12D blockade in pancreatic cancer through vertical pathway inhibition - PubMed
4 days ago
- #Pancreatic Cancer
- #Adaptive Resistance
- #KRASG12D
- KRASG12D mutations are prevalent in over 90% of pancreatic ductal adenocarcinoma (PDAC) cases.
- Mutant-selective KRASG12D inhibitors show initial clinical promise but face adaptive resistance challenges.
- Resistance mechanisms vary: EGFR drives RAS-MAPK reactivation in epithelial PDAC models, while FGFR signaling is key in mesenchymal models.
- A RAS(ON) multi-selective inhibitor, targeting both wild-type and mutant RAS, effectively counters resistance across different PDAC models.
- Combining mutant-selective KRAS inhibitors with RAS(ON) inhibitors may offer a universal strategy to overcome adaptive resistance in PDAC.