Combined targeting of G protein‐coupled receptor and <scp>EGF</scp> receptor signaling overcomes resistance to <scp>PI</scp> 3K pathway inhibitors in <scp>PTEN</scp> ‐null triple negative breast cancer

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 (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 βγ subunits and also epidermal growth factor receptor (EGFR) for the activation of the PI3K isoform p110β and AKT. Compensation mechanisms involving these two branches of the pathway could bypass PI3K blockade, but combination targeting of both EGFR and PI3Kβ 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.