Disruption of the interaction of RAS with PI 3-kinase induces regression of EGFR-mutant-driven lung cancer
journal contributionposted on 07.09.2020, 11:15 by Miguel M Murillo, Sareena Rana, Bradley Spencer-Dene, Emma Nye, Gordon Stamp, Julian Downward
RAS family GTPases contribute directly to the regulation of type I phosphoinositide 3-kinases (PI3Ks) via RAS-binding domains in the PI3K catalytic p110 subunits. Disruption of this domain of p110α impairs RAS-mutant-oncogene-driven tumor formation and maintenance. Here, we test the effect of blocking the interaction of RAS with p110α on epidermal growth factor receptor (EGFR)-mutant-driven lung tumorigenesis. Disrupting the RAS-PI3K interaction inhibits activation of both AKT and RAC1 in EGFR-mutant lung cancer cells, leading to reduced growth and survival, and inhibits EGFR-mutant-induced tumor onset and promotes major regression of established tumors in an autochthonous mouse model of EGFR-mutant-induced lung adenocarcinoma. The RAS-PI3K interaction is thus an important signaling node and potential therapeutic target in EGFR-mutant lung cancer, even though RAS oncogenes are not themselves mutated in this setting, suggesting different strategies for tackling tyrosine kinase inhibitor resistance in lung cancer.
EGFRKRASPI3KPIK3CARAC1RASlung cancerAnimalsCell Line, TumorCell ProliferationDisease Models, AnimalEpidermal Growth FactorErbB ReceptorsHumansLung NeoplasmsMice, Inbred C57BLMutationPhosphatidylinositol 3-KinasesProtein BindingProtein Domainsras ProteinsDownward FC001070HP0601 Biochemistry and Cell Biology