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.
journal_name
Cell Repjournal_title
Cell reportsauthors
Murillo MM,Rana S,Spencer-Dene B,Nye E,Stamp G,Downward Jdoi
10.1016/j.celrep.2018.12.003subject
Has Abstractpub_date
2018-12-26 00:00:00pages
3545-3553.e2issue
13issn
2211-1247pii
S2211-1247(18)31914-4journal_volume
25pub_type
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