"TFAP2C-DDR1 axis regulates resistance to CDK4/6 inhibitor in breast ca" by Muhammad Jameel Mughal, Yi Zhang et al.
 

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

Muhammad Jameel Mughal, Department of Biochemistry and Molecular Medicine, GWU Cancer Center, George Washington University School of Medicine and Health Sciences, Washington, DC, 20037, USA.
Yi Zhang, Department of Biochemistry and Molecular Medicine, GWU Cancer Center, George Washington University School of Medicine and Health Sciences, Washington, DC, 20037, USA.
Zhuqing Li, Department of Biochemistry and Molecular Medicine, GWU Cancer Center, George Washington University School of Medicine and Health Sciences, Washington, DC, 20037, USA.
Shuyan Zhou, Department of Biochemistry and Molecular Medicine, GWU Cancer Center, George Washington University School of Medicine and Health Sciences, Washington, DC, 20037, USA.
Changmin Peng, Department of Biochemistry and Molecular Medicine, GWU Cancer Center, George Washington University School of Medicine and Health Sciences, Washington, DC, 20037, USA.
Ya-Qin Zhang, Early Translation Branch, Division of Preclinical Innovation, National Center for Translational Sciences (NCATS), National Institutes of Health (NIH), Rockville, MD, 20850, USA.
Edward Seto, Department of Biochemistry and Molecular Medicine, GWU Cancer Center, George Washington University School of Medicine and Health Sciences, Washington, DC, 20037, USA.
Min Shen, Early Translation Branch, Division of Preclinical Innovation, National Center for Translational Sciences (NCATS), National Institutes of Health (NIH), Rockville, MD, 20850, USA.
Matthew D. Hall, Early Translation Branch, Division of Preclinical Innovation, National Center for Translational Sciences (NCATS), National Institutes of Health (NIH), Rockville, MD, 20850, USA.
Wenge Zhu, Department of Biochemistry and Molecular Medicine, GWU Cancer Center, George Washington University School of Medicine and Health Sciences, Washington, DC, 20037, USA. Electronic address: wz6812@gwu.edu.

Document Type

Journal Article

Publication Date

11-26-2024

Journal

Cancer letters

Volume

610

DOI

10.1016/j.canlet.2024.217356

Keywords

Breast cancer; CDK4/6 inhibitors; DDR1; Resistance; TFAP2C

Abstract

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.

Department

Biochemistry and Molecular Medicine

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