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

Autor: Mughal MJ; Department of Biochemistry and Molecular Medicine, GWU Cancer Center, George Washington University School of Medicine and Health Sciences, Washington, DC, 20037, USA., Zhang Y; Department of Biochemistry and Molecular Medicine, GWU Cancer Center, George Washington University School of Medicine and Health Sciences, Washington, DC, 20037, USA., Li Z; Department of Biochemistry and Molecular Medicine, GWU Cancer Center, George Washington University School of Medicine and Health Sciences, Washington, DC, 20037, USA., Zhou S; Department of Biochemistry and Molecular Medicine, GWU Cancer Center, George Washington University School of Medicine and Health Sciences, Washington, DC, 20037, USA., Peng C; Department of Biochemistry and Molecular Medicine, GWU Cancer Center, George Washington University School of Medicine and Health Sciences, Washington, DC, 20037, USA., Zhang YQ; Early Translation Branch, Division of Preclinical Innovation, National Center for Translational Sciences (NCATS), National Institutes of Health (NIH), Rockville, MD, 20850, USA., Seto E; Department of Biochemistry and Molecular Medicine, GWU Cancer Center, George Washington University School of Medicine and Health Sciences, Washington, DC, 20037, USA., Shen M; Early Translation Branch, Division of Preclinical Innovation, National Center for Translational Sciences (NCATS), National Institutes of Health (NIH), Rockville, MD, 20850, USA., Hall MD; Early Translation Branch, Division of Preclinical Innovation, National Center for Translational Sciences (NCATS), National Institutes of Health (NIH), Rockville, MD, 20850, USA., Zhu W; 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.
Jazyk: angličtina
Zdroj: Cancer letters [Cancer Lett] 2025 Feb 01; Vol. 610, pp. 217356. Date of Electronic Publication: 2024 Nov 26.
DOI: 10.1016/j.canlet.2024.217356
Abstrakt: 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.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this manuscript titled “TFAP2C-DDR1 Axis Regulates Resistance to CDK4/6 Inhibitors in Breast Cancer."
(Copyright © 2024 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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