BioCentury
ARTICLE | Distillery Therapeutics

Combined inhibition of EGFR and RAF1 for mutant-KRAS, mutant TP53-driven PDAC

April 22, 2019 5:25 PM UTC

INDICATION: Pancreatic cancer

Cell culture and mouse studies suggest dual inhibition of EGFR and CRAF could help treat KRAS- and p53-mutant pancreatic ductal adenocarcinoma (PDAC). In nine patient-derived KRAS- and p53-mutant PDAC cells lines, two shRNAs against EGFR plus two shRNAs against CRAF decreased proliferation compared with a scrambled shRNA. In a mouse model of KRAS- and p53-mutant PDAC, tumor-specific knockout of EGFR and CRAF decreased tumorigenesis and increased survival compared with EGFR or RAF1 knockout alone. In another mouse model of the dual-mutant PDAC, systemic knockout of EGFR and CRAF decreased tumor size compared with normal EGFR and CRAF expression. In nine patient-derived xenograft mouse models of dual-mutant PDAC, two shRNA against RAF1 plus the EGFR inhibitors Iressa gefitinib or Tarceva erlotinib decreased tumor cell proliferation compared with scrambled shRNA plus vehicle. Next steps could include testing CRAF inhibitors in combination with EGFR inhibitors in KRAS- and p53-mutant PDAC...