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

Ozge Saatci, Metin Cetin, Meral Uner, Unal Metin Tokat, Ioulia Chatzistamou, Pelin Gulizar Ersan, Elodie Montaudon, Aytekin Akyol, Sercan Aksoy, Aysegul Uner, Elisabetta Marangoni, Mathew Sajish and Ozgur Sahin ()
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Ozge Saatci: Hollings Cancer Center, Medical University of South Carolina
Metin Cetin: Hollings Cancer Center, Medical University of South Carolina
Meral Uner: Hacettepe University
Unal Metin Tokat: Bilkent University
Ioulia Chatzistamou: University of South Carolina
Pelin Gulizar Ersan: University of South Carolina
Elodie Montaudon: PSL Research University
Aytekin Akyol: Hacettepe University
Sercan Aksoy: Hacettepe University Cancer Institute
Aysegul Uner: Hacettepe University
Elisabetta Marangoni: PSL Research University
Mathew Sajish: University of South Carolina
Ozgur Sahin: Hollings Cancer Center, Medical University of South Carolina

Nature Communications, 2023, vol. 14, issue 1, 1-20

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-42736-y

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