PARP inhibitors are active in tumors with defects in DNA homologous recombination (HR) due to BRCA1/2 mutations. The phosphoinositide 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 show 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 the growth of tumors displaying BRCA1/2 downregulation following PI3K inhibition. PI3K-mediated BRCA downregulation was accompanied by extracellular signal–regulated kinase (ERK) phosphorylation. Overexpression of an active form of MEK1 resulted in ERK activation and downregulation of BRCA1, whereas 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 knockdown of ETS1 led to increased BRCA1/2 expression, limiting the sensitivity to combined BKM120 and olaparib in 3-dimensional culture. SIGNIFICANCE Treatment options are limited for patients with TNBCs. PARP inhibitors have clinical activity restricted to a small subgroup of patients with BRCA mutations. Here, we show that PI3K blockade results in HR impairment and sensitization to PARP inhibition in TNBCs without BRCA mutations, providing a rationale to combine PI3K and PARP inhibitors in this indication. Our findings could greatly expand the number of patients with breast cancer that would benefit from therapy with PARP inhibitors. On the basis of our findings, a clinical trial with BKM120 and olaparib is being initiated in patients with TNBCs.

Background: Racial inequities for patients with heart failure (HF) have been widely documented. HF patients who receive cardiology care during a hospital admission have better outcomes. It is unknown whether there are differences in admission to a cardiology or general medicine service by race. This study examined the relationship between race and admission service, and its effect on 30-day readmission and mortality Methods: We performed a retrospective cohort study from September 2008 to November 2017 at a single large urban academic referral center of all patients self-referred to the emergency department and admitted to either the cardiology or general medicine service with a principal diagnosis of HF, who self-identified as white, black, or Latinx. We used multivariable generalized estimating equation models to assess the relationship between race and admission to the cardiology service. We used Cox regression to assess the association between race, admission service, and 30-day readmission and mortality. Results: Among 1967 unique patients (66.7% white, 23.6% black, and 9.7% Latinx), black and Latinx patients had lower rates of admission to the cardiology service than white patients (adjusted rate ratio, 0.91; 95% CI, 0.84–0.98, for black; adjusted rate ratio, 0.83; 95% CI, 0.72–0.97 for Latinx). Female sex and age >75 years were also independently associated with lower rates of admission to the cardiology service. Admission to the cardiology service was independently associated with decreased readmission within 30 days, independent of race. Conclusions: Black and Latinx patients were less likely to be admitted to cardiology for HF care. This inequity may, in part, drive racial inequities in HF outcomes.

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