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Cell Rep. 2018 Dec 26;25(13):3545-3553.e2. doi: 10.1016/j.celrep.2018.12.003.

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

Author information

1
Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK; Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
2
Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK.
3
Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
4
Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK; Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK. Electronic address: julian.downward@crick.ac.uk.

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.

KEYWORDS:

EGFR; KRAS; PI3K; PIK3CA; RAC1; RAS; lung cancer

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