c-myc regulates the sensitivity of breast cancer cells to palbociclib via c-myc/miR-29b-3p/CDK6 axis

Palbociclib, a CDK4/6 inhibitor, has been granted accelerated approval by US FDA for hormone receptor-positive HER2-negative metastatic breast Cancer. To determine potential biomarkers of palbociclib sensitivity to assist in patient selection and clinical development, we investigated the effects of palbociclib in a panel of molecularly characterized breast Cancer cell lines. We quantified palbociclib sensitivity and c-Myc expression in 11 breast Cancer cell lines, 124 breast Cancer samples, and The Cancer Genome Atlas database. We found non-TNBC subtypes were more sensitive to palbociclib than TNBC. Activation of c-Myc led to differential palbociclib sensitivities, and further inhibition of c-Myc enhanced palbociclib sensitivity. Moreover, we identified for the first time a c-Myc/miR-29b-3p/CDK6 axis in breast Cancer that could be responsible for c-myc-induced palbociclib insensitivity, in which c-Myc activation resulted in downregulation of miR-29b-3p, further activated CDK6 and inhibited cell-cycle arrest at G₁ phase. Moreover, downregulated (inactived) c-myc-induced oncogenic addiction could increase palbociclib efficacy, using both Xenograft model and patient-derived tumor xenograft (PDTX) model. Our finding extends the concept of combined blockade of the CDK4/6 and c-Myc signaling pathways to increase palbociclib sensitivity, making c-Myc a promising biomarker for palbociclib sensitivity in breast Cancer.