Open AccessCombined targeting of G protein‐coupled receptor and EGF receptor signaling overcomes resistance to PI 3K pathway inhibitors in PTEN ‐null triple negative breast cancer
Author(s) -
Zecchin Davide,
Moore Christopher,
Michailidis Fanourios,
Horswell Stuart,
Rana Sareena,
Howell Michael,
Downward Julian
Publication year - 2020
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.202011987
Subject(s) - oncogene , pten , biology , library science , cancer , genetics , pi3k/akt/mtor pathway , computer science , cell cycle , signal transduction
Triple‐negative breast cancer ( TNBC ) has poorer prognosis compared to other types of breast cancers due to the lack of effective therapies and markers for patient stratification. Loss of PTEN tumor suppressor gene expression is a frequent event in TNBC , resulting in over‐activation of the PI 3‐kinase ( PI 3K) pathway and sensitivity to its inhibition. However, PI 3K pathway inhibitors show limited efficacy as monotherapies on these tumors. We report a whole‐genome screen to identify targets whose inhibition enhanced the effects of different PI 3K pathway inhibitors on PTEN ‐null TNBC . This identified a signaling network that relies on both the G protein‐coupled receptor for thrombin ( PAR 1/F2R) and downstream G protein βγ subunits and also epidermal growth factor receptor ( EGFR ) for the activation of the PI 3K isoform p110β and AKT . Compensation mechanisms involving these two branches of the pathway could bypass PI 3K blockade, but combination targeting of both EGFR and PI 3Kβ suppressed ribosomal protein S6 phosphorylation and exerted anti‐tumor activity both in vitro and in vivo, suggesting a new potential therapeutic strategy for PTEN ‐null TNBC .