Poly (ADP-ribose) polymerase (PARP) inhibitors provide a promising therapeutic strategy for triple-negative breast cancers (TNBCs) with BRCA1/2 mutation. However, acquire resistance mechanisms and genetic alterations limit the clinical efficacy of PARP inhibitors. The aberrant activation of phosphatidylinositol 3-kinase (PI3K) is a significant problem for cancer development and thus the inhibition of PI3K by PI3K inhibitors is a novel targeted therapy in advanced breast cancer. Here, we, for the first time, investigated that the combined inhibition of PARP by Talazoparib (TAL) and PI3K by LY294002 synergistically inhibited proliferation of BRCA1 mutant HCC1937 TNBC cells through apoptosis, G0/G1 arrest, oxidative stress and increased DNA damage compared to drug alone. Additionally, TAL and LY294002 combination could be a promising strategy for overcoming TAL resistance. Co-treatment of TAL with LY294002 considerably suppressed the activation of PI3K, Akt1 and mTOR expression and phosphorylated protein levels in TNBC cells and caused changes in the multiple kinase phosphorylation. Our findings revealed that the dual inhibition of PARP and PI3K might represent an effective therapeutic strategy for TNBC and potentially overcome TAL resistance.Keywords:Combination therapy; Phosphatidylinositol 3-kinase (PI3K); Poly (ADP-ribose) polymerase (PARP) inhibitors; Talazoparib; Triple negative breast cancer.