KRAS Codon-Specific Mutations Differentially Toggle PI3K Pathway Signaling and Alter Sensitivity to Inavolisib (GDC-0077).

ABSTRACT: PIK3CA and KRAS are among the most frequently mutated oncogenes and often co-mutated in colorectal cancers. Understanding the impact of KRAS codon-specific mutations on cross-talks between the PI3K and MAPK pathways and response to targeted therapies, such as the p110α-specific inhibitor inavolisib (GDC-0077), is critical for advancing precision oncology. Focusing on colorectal PIK3CA + KRAS co-mutated models, we found that KRASG12D-mutated cells were more sensitive to inavolisib than models with KRASG13D, or other MAPK pathway mutations, even though the PI3K and MAPK pathways were active in both genotypes. In most co-mutated models, regardless of the type of KRAS alteration, the combination of inavolisib with MAPK pathway inhibitors showed synergy in vitro and in vivo. Our work highlights

SUBMITTER: Song KW 

PROVIDER: S-EPMC12670073 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature