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Background  PARP inhibitors (PARPi) benefit only a fraction of breast cancer patients with BRCA mutations, and their efficacy is even more limited in triple-negative breast cancer (TNBC) due to clinical primary and acquired resistance. Here, we found that the efficacy of the PARPi olaparib in TNBC can be improved by combination with the CDK4/6 inhibitor (CDK4/6i) palbociclib.    Methods  We screened primary olaparib-sensitive and olaparib-resistant cell lines from existing BRCA mut /TNBC cell lines and generated cells with acquired olaparib resistance by gradually increasing the concentration. The effects of the PARPi olaparib and the CDK4/6i palbociclib on BRCA mut /TNBC cell lines were examined in both sensitive and resistant cells in vitro and in vivo. Pathway and gene alterations were assessed mechanistically and pharmacologically.    Results  We demonstrated for the first time that the combination of olaparib and palbociclib has synergistic effects against BRCA mut /TNBC both in vitro and in vivo. In olaparib-sensitive MDA-MB-436 cells, the single agent olaparib significantly inhibited cell viability and affected cell growth due to severe DNA damage. In olaparib-resistant HCC1937 and SUM149 cells, single-agent olaparib was ineffective due to potential homologous recombination (HR) repair, and the combination of olaparib and palbociclib greatly inhibited HR during the G2 phase, increased DNA damage and inhibited tumour growth. Inadequate DNA damage caused by olaparib activated the Wnt signalling pathway and upregulated MYC. Further experiments indicated that the overexpression of β-catenin, especially its hyperphosphorylation at the Ser675 site, activated the Wnt signalling pathway and mediated olaparib resistance, which could be strongly inhibited by combined treatment with palbociclib.    Conclusions  Our data provide a rationale for clinical evaluation of the therapeutic synergy of the PARPi olaparib and CDK4/6i palbociclib in BRCA mut /TNBCs with high Wnt signalling activation and high MYC expression that do not respond to PARPi monotherapy.    Supplementary Information  The online version contains supplementary material available at 10.1186/s13046-021-01930-w.

Efficacy and mechanism of the combination of PARP and CDK4/6 inhibitors in the treatment of triple-negative breast cancer