Mifepristone modulates response to CDK4/6 inhibition in progesterone receptor isoform A-high breast cancer models

Abstract CDK4/6 inhibitors have significantly improved outcomes in estrogen receptor–positive breast cancer. Mifepristone, a progesterone receptor (PR) antagonist, is under investigation in tumors with high levels of PR isoform A (PRA). Here, we evaluated the therapeutic potential of combining mifepristone with CDK4/6 inhibitors. Mifepristone enhanced CDK4/6 inhibitor efficacy in PRA-expressing T47D and T47D-YA cells, whereas it increased proliferation in PR isoform B-overexpressing T47D-YB cells; however, palbociclib retained antiproliferative activity. The combination reduced proliferation through RB dephosphorylation and E2F1 downregulation. ChIP–qPCR and transient transfection assays suggested a direct effect of mifepristone on E2F1 transcription. Ex vivo treatment of breast cancer tissue slices from two of three tumors with high PRA levels showed optimal inhibition with the combination, while complete inhibition was observed with all treatments in the third tumor. Consistent effects were obtained in T47D xenografts in vivo. In murine PR+ mammary carcinomas, sensitivity to palbociclib was independent of responsiveness to mifepristone. Palbociclib sensitivity correlated with elevated CDKN2C expression, whereas resistance was associated with increased NOTCH1 expression. Importantly, pharmacologic Notch inhibition restored palbociclib sensitivity in resistant cells. These findings suggest that mifepristone may potentiate CDK4/6 inhibition in PRA-high breast cancers and identify the Notch pathway as a mediator of intrinsic palbociclib resistance.