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  3. Toxic PARP trapping upon cAMP-induced DNA damage reinstates the efficacy of endocrine therapy and CDK4/6 inhibitors in treatment-refractory ER+ breast cancer

Toxic PARP trapping upon cAMP-induced DNA damage reinstates the efficacy of endocrine therapy and CDK4/6 inhibitors in treatment-refractory ER+ breast cancer

  • Nat Commun. 2023 Nov 2;14(1):6997. doi: 10.1038/s41467-023-42736-y.
Ozge Saatci 1 2,  Metin Cetin 1 2,  Meral Uner 3,  Unal Metin Tokat 4,  Ioulia Chatzistamou 5,  Pelin Gulizar Ersan 2,  Elodie Montaudon 6,  Aytekin Akyol 3,  Sercan Aksoy 7,  Aysegul Uner 3,  Elisabetta Marangoni 6,  Mathew Sajish 2,  Ozgur Sahin 8 9
Affiliations

Affiliations

  • 1 Department of Biochemistry and Molecular Biology, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, 29425, USA.
  • 2 Department of Drug Discovery and Biomedical Sciences, University of South Carolina, Columbia, SC, 29208, USA.
  • 3 Department of Pathology, Faculty of Medicine, Hacettepe University, 06100, Ankara, Turkey.
  • 4 Department of Molecular Biology and Genetics, Bilkent University, Ankara, 06800, Turkey.
  • 5 Department of Pathology, Microbiology & Immunology, University of South Carolina, Columbia, SC, 29208, USA.
  • 6 Translational Research Department, Institut Curie, PSL Research University, Paris, 75005, France.
  • 7 Department of Medical Oncology, Hacettepe University Cancer Institute, 06100, Ankara, Turkey.
  • 8 Department of Biochemistry and Molecular Biology, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, 29425, USA. sahin@musc.edu.
  • 9 Department of Drug Discovery and Biomedical Sciences, University of South Carolina, Columbia, SC, 29208, USA. sahin@musc.edu.
PMID: 37914699 DOI: 10.1038/s41467-023-42736-y
Abstract

Resistance to endocrine therapy and CDK4/6 inhibitors, the standard of care (SOC) in estrogen receptor-positive (ER+) breast Cancer, greatly reduces patient survival. Therefore, elucidating the mechanisms of sensitivity and resistance to SOC therapy and identifying actionable targets are urgently needed. Here, we show that SOC therapy causes DNA damage and toxic PARP1 trapping upon generation of a functional BRCAness (i.e., BRCA1/2 deficiency) phenotype, leading to increased histone parylation and reduced H3K9 acetylation, resulting in transcriptional blockage and cell death. Mechanistically, SOC therapy downregulates phosphodiesterase 4D (PDE4D), a novel ER target gene in a feedforward loop with ER, resulting in increased cAMP, PKA-dependent phosphorylation of mitochondrial COXIV-I, ROS generation and DNA damage. However, during SOC resistance, an ER-to-EGFR switch induces PDE4D overexpression via c-Jun. Notably, combining SOC with inhibitors of PDE4D, EGFR or PARP1 overcomes SOC resistance irrespective of the BRCA1/2 status, providing actionable targets for restoring SOC efficacy.

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