PI3K inhibition impairs BRCA1/2 expression and sensitizes BRCA proficient triple negative breast cancer to PARP inhibition
Menées à l'aide de modèles murins et de xénogreffes, ces deux études suggèrent l'efficacité d'un traitement combinant un inhibiteur de PARP et un inhibiteur de PI3K dans les cancers du sein triplement négatifs ou présentant une mutation de BRCA1
Poly-ADP-ribose-polymerase (PARP) inhibitors are active in tumors with defects in DNA homologous recombination (HR) due to BRCA1/2 mutations. The phosphatidylinositol 3-kinase (PI3K) signaling pathway preserves HR steady state. We hypothesized that in BRCA proficient Triple Negative Breast Cancer (TNBC), PI3K inhibition would result in HR impairment and subsequent sensitization to PARP inhibitors. We demonstrate in TNBC cells that PI3K inhibition leads to DNA damage, downregulation of BRCA1/2, gain in poly-ADP-ribosylation and subsequent sensitization to PARP inhibition. In TNBC patient-derived primary tumor xenografts, dual PI3K and PARP inhibition with BKM120 and olaparib reduced tumor growth in tumors displaying BRCA1/2 downregulation following PI3K inhibition. PI3K-mediated BRCA downregulation was accompanied by ERK phosphorylation. Overexpression of an active form of MEK1 resulted in ERK activation and downregulation of BRCA1, while the MEK inhibitor AZD6244 increased BRCA1/2 expression and reversed the effects of MEK1. We subsequently identified that the ETS1 transcription factor was involved in the ERK-dependent BRCA1/2 downregulation and that knock-down of ETS1 led to increased BRCA1/2 expression, limiting the sensitivity to combined BKM120 and olaparib in 3D culture.
Cancer Discovery , résumé, 2012