BioCentury
ARTICLE | Distillery Therapeutics

KRAS inhibitor combinations for improved therapeutic efficacy

August 23, 2019 12:03 AM UTC

INDICATION: Lung cancer, pancreatic cancer

UCSF’s Kevan Shokat and colleagues have identified two sets of genes for which inhibition could improve the efficacy of KRAS G12C inhibitors. Through a CRISPR-based screen in human lung and pancreatic cancer cells treated with a KRAS G12C inhibitor tool compound for genes supporting cell viability, they identified a set of genes, including FGFR1, EGFR and SHP-2, that are associated with the regulation of KRAS activity; and a second set including cyclin D1 (CCND1;BCL1), CDK4 and PI3K that promotes cell growth and survival. A combination of EGFR inhibitor Tarceva erlotinib, PI3K inhibitor buparlisib, dual CDK4/CDK6 inhibitor Ibrance palbociclib, FGFR inhibitor AZD4547 or SHP-2 inhibitor SHP099 with the KRAS G12C inhibitor killed more cultured lung and pancreatic cells than the KRAS G12C inhibitor alone. In xenograft mouse models of lung and pancreatic cancer, the KRAS G12C inhibitor plus Tarceva or Ibrance suppressed tumor growth compared with any of the compounds in monotherapy...