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

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buir.contributor.authorTokat, Ünal Metin
buir.contributor.orcidTokat, Ünal Metin|0000-0003-0026-368X
dc.citation.epage6997-20en_US
dc.citation.issueNumber1
dc.citation.spage6997-1
dc.citation.volumeNumber14
dc.contributor.authorSaatci, O.
dc.contributor.authorCetin, M
dc.contributor.authorUner, M.
dc.contributor.authorTokat, Ünal Metin
dc.contributor.authorChatzistamou, I.
dc.contributor.authorErsan, P. G.
dc.contributor.authorMontaudon, E.
dc.contributor.authorAkyol, A.
dc.contributor.authorAksoy, S.
dc.contributor.authorUner, A.
dc.contributor.authorMarangoni, E.
dc.contributor.authorSajish, M.
dc.date.accessioned2024-03-21T16:52:38Z
dc.date.available2024-03-21T16:52:38Z
dc.date.issued2023-11-02
dc.description.abstractResistance 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. © 2023, The Author(s).
dc.description.provenanceMade available in DSpace on 2024-03-21T16:52:38Z (GMT). No. of bitstreams: 1 Toxic_PARP_trapping_upon_cAMP-induced_DNA_damage_reinstates_the_efficacy_of_endocrine_therapy_and_CDK46_inhibitors_in_treatment-refractory_ER+_breast_cancer.pdf: 11394548 bytes, checksum: 483d5fee7aab5a3b6723adfb6678af14 (MD5) Previous issue date: 2023-11-02en
dc.identifier.doi10.1038/s41467-023-42736-y
dc.identifier.eissn2041-1723
dc.identifier.urihttps://hdl.handle.net/11693/115054
dc.language.isoen_US
dc.publisherNature Research
dc.relation.isversionofhttps://dx.doi.org/10.1038/s41467-023-42736-y
dc.rightsCC BY 4.0 DEED (Attribution 4.0 International)
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.source.titleNature Communications
dc.titleToxic PARP trapping upon cAMP-induced DNA damage reinstates the efficacy of endocrine therapy and CDK4/6 inhibitors in treatment-refractory ER+ breast cancer
dc.typeArticle

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