Disruption of the Interaction of RAS with PI 3-Kinase Induces Regression of EGFR-Mutant-Driven Lung Cancer

Summary

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.

Graphical Abstract

Highlights

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  Disrupting the interaction of PI 3-kinase with RAS impairs EGF activation of AKT and RAC

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  Mice bred with RAS-binding-domain-defective PI 3-kinase and activated EGFR mutant

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  Abrogating RAS binding to PI 3-kinase blocks EGFR-induced lung tumor initiation

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  Blocking the RAS-PI 3-kinase interaction induces regression of EGFR-induced tumors

Abstract

The interaction between RAS and PI 3-kinase is essential for RAS-mutant-induced carcinogenesis. Murillo et al. show that in EGFR-mutant-driven lung cancer, disruption of the interaction of PI 3-kinase with normal RAS proteins blocks tumor initiation and promotes regression of existing tumors, highlighting an unexpected vulnerability of EGFR-driven lung cancer.