Journal
EMBO MOLECULAR MEDICINE
Volume 12, Issue 8, Pages -Publisher
WILEY
DOI: 10.15252/emmm.202011987
Keywords
G protein; p110 beta; PTEN; resistance; triple-negative breast cancer
Categories
Funding
- Francis Crick Institute - Cancer Research UK [FC001070]
- Francis Crick Institute - UK Medical Research Council [FC001070]
- Francis Crick Institute - Wellcome Trust [FC001070]
- European Research Council
- Wellcome Trust [103799/Z/14/Z]
- Fondazione Umberto Veronesi-Young Investigator Programme
- BBSRC [BB/R013799/1] Funding Source: UKRI
- Wellcome Trust [103799/Z/14/Z] Funding Source: Wellcome Trust
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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 overactivation of the PI 3-kinase (PI3K) pathway and sensitivity to its inhibition. However, PI3K 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 PI3K pathway inhibitors on PTEN-null TNBC. This identified a signaling network that relies on both the G protein-coupled receptor for thrombin (PAR1/F2R) and downstream G protein beta gamma subunits and also epidermal growth factor receptor (EGFR) for the activation of the PI3K isoform p110 beta and AKT. Compensation mechanisms involving these two branches of the pathway could bypass PI3K blockade, but combination targeting of both ECFR and PI3K beta suppressed ribosomal protein S6 phosphorylation and exerted antitumor activity both in vitro and in vivo, suggesting a new potential therapeutic strategy for PTEN-null TNBC.
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