RUNX1-PDGFBB-AKT pathway mediated CDK4/6 inhibitor resistance in HR+/HER2- breast cancer

Cyclin-dependent kinases 4 and 6 (CDK4/6) are essential drivers of the cell cycle and are also critical for the initiation and progression of diverse malignancies. Pharmacological inhibitors targeting CDK4/6 have demonstrated significant activity against various tumor types such as breast cancer. However, resistance to CDK4/6 inhibitors (CDK4/6i) (such as palbociclib) remain an immense obstacle in clinical and the underlying mechanisms have not been fully understood. Using Conditional medium co-culture, quantitative high-throughput combinational screen (qHTCS), and genomic sequencing, we report that the RUNX1-PDGFBB-AKt pathway was significantly elevated in palbociclib-resistance cells. Inhibition of this axis can enhance the therapeutic efficacy of Palbociclib and surmount Palbociclib resistance both in vitro and in vivo. Mechanistically, we found that O-GlcNAc transferase (OGT) modifies RUNX1 with O-GlcNAcylation at Serine 252 (Ser252), thereby stabilizing RUNX1 protein expression, which is crucial in regulating PDGFBB expression. Significantly, clinical studies also confirm that RUNX1-PDGFBB-Akt pahtway was elevated in palbociclib-resistance patients. Collectively, these results reveal a previously unrecognized mechanism by which RUNX1-PDGFBB mediated palbociclib resistance, and provide valuable insights for the development of innovative therapeutic strategies in future clinical contexts. To investigate the mechanism of Palbociclib resistance in breast cancer cell lines, we first generated Palbociclib-resistant (PR) cell line MCF-7 PR. Then we compare different genes expression between MCF-7-PR cells and MCF-7 PR-siPDGFB cells by RNA seq.