Disruption of the Interaction of RAS with PI 3-Kinase Induces Regression of EGFR-Mutant-Driven Lung Cancer.
Abstract
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.
Collections
Subject
Cell Line, Tumor
Animals
Mice, Inbred C57BL
Humans
Lung Neoplasms
Disease Models, Animal
Epidermal Growth Factor
ras Proteins
Cell Proliferation
Protein Binding
Mutation
Phosphatidylinositol 3-Kinases
ErbB Receptors
Protein Domains
Research team
Experimental Pathology
Lung Cancer Group
Language
eng
Date accepted
2018-11-30
License start date
2018-12
Citation
Cell reports, 2018, 25 (13), pp. 3545 - 3553.e2