TFAP2C-DDR1 axis regulates resistance to CDK4/6 inhibitor in breast cancer

Breast cancer is the predominant malignancy with the majority of cases are characterized as HR+/HER2-subtype. Although cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) have shown remarkable efficacy in treating this subtype when combined with endocrine therapy, the development of resistance to these inhibitors remains a significant clinical obstacle. Hence, there is an urgent need to explore innovative therapies and decipher the underlying mechanisms of resistance to CDK4/6i. In this study, we employed quantitative high-throughput combination screening (qHTCS) and genomics/proteomics approaches to uncover the molecular mechanisms driving resistance to CDK4/6i (palbociclib) in breast cancer. The comprehensive analyses revealed DDR1 as a potential factor implicated in mediating resistance to CDK4/6i. Specifically, DDR1 inhibition in combination with palbociclib exhibited remarkable synergistic effects, reducing cell survival signaling and promoting apoptosis in resistant cells. In-vivo xenograft model further validated the synergistic effects, showing a significant reduction in the resistant tumor growth. Exploration into DDR1 activation uncovered TFAP2C as a key transcription factor regulating DDR1 expression in palbociclib resistant cells and inhibition of TFAP2C re-sensitized resistant cells to palbociclib. Gene set enrichment analysis (GSEA) in the NeoPalAna trial demonstrated a significant enrichment of the TFAP2C-DDR1 gene set from patitens after palbociclib treatment, suggesting the possible activation of the TFAP2C-DDR1 axis following palbociclib exposure. Overall, this study provides crucial insights into the novel molecular landscape of palbociclib resistance in breast cancer, suggesting TFAP2C-DDR1 axis inhibition as a promising strategy to overcome resistance.