Abstract
BackgroundPARP 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.MethodsWe screened primary olaparib-sensitive and olaparib-resistant cell lines from existing BRCAmut/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 BRCAmut/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.ResultsWe demonstrated for the first time that the combination of olaparib and palbociclib has synergistic effects against BRCAmut/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.ConclusionsOur data provide a rationale for clinical evaluation of the therapeutic synergy of the PARPi olaparib and CDK4/6i palbociclib in BRCAmut/TNBCs with high Wnt signalling activation and high MYC expression that do not respond to PARPi monotherapy.
Highlights
poly-(ADP)-ribose polymerase (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
Olaparib and palbociclib synergistically inhibit the growth of BRCAmut/TNBCs, especially olaparib-resistant cell lines To evaluate the effects of the concomitant inhibition of PARP and CDK4/6, we assessed the response of a panel of 8 TNBC cell lines, including 3 luminal androgen receptor (LAR) subtype cell lines and 3 BRCAmut cell lines, to olaparib and palbociclib as single agents and in combination
Consistent with previous literature, the IC50 of the CDK4/6 inhibitor (CDK4/6i) palbociclib in the LAR subtype was lower than that in other TNBC subtypes (IC50: 9.523 ± 1.317 μM vs 3.203 ± 0.9261 μM, p = 0.0153)
Summary
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. 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 BRCAmut/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 BRCAmut/TNBC cell lines were examined in both sensitive and resistant cells in vitro and in vivo. The clinical targeted drugs for BC include poly-(ADP)-ribose polymerase (PARP) inhibitors (PARPi), CDK4/6 inhibitors (CDK4/6i), PI3K inhibitors, and AKT inhibitors, but none of these drugs alone is very effective against TNBC. There is an urgent need for the rational exploration of drug compatibility and potential targets for TNBC in the future [5, 6]
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