Toxic PARP trapping upon cAMP-induced DNA damage reinstates the efficacy of endocrine therapy and CDK4/6 inhibitors in treatment-refractory ER+ breast cancer
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 ur...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-11-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-42736-y |
| _version_ | 1797636797103079424 |
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| author | 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 Ozgur Sahin |
| author_facet | 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 Ozgur Sahin |
| author_sort | Ozge Saatci |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-11T12:39:18Z |
| format | Article |
| id | doaj.art-12ad9995bcd94038ac3e1cc764cb8625 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-11T12:39:18Z |
| publishDate | 2023-11-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-12ad9995bcd94038ac3e1cc764cb86252023-11-05T12:22:40ZengNature PortfolioNature Communications2041-17232023-11-0114112010.1038/s41467-023-42736-yToxic PARP trapping upon cAMP-induced DNA damage reinstates the efficacy of endocrine therapy and CDK4/6 inhibitors in treatment-refractory ER+ breast cancerOzge Saatci0Metin Cetin1Meral Uner2Unal Metin Tokat3Ioulia Chatzistamou4Pelin Gulizar Ersan5Elodie Montaudon6Aytekin Akyol7Sercan Aksoy8Aysegul Uner9Elisabetta Marangoni10Mathew Sajish11Ozgur Sahin12Department of Biochemistry and Molecular Biology, Hollings Cancer Center, Medical University of South CarolinaDepartment of Biochemistry and Molecular Biology, Hollings Cancer Center, Medical University of South CarolinaDepartment of Pathology, Faculty of Medicine, Hacettepe UniversityDepartment of Molecular Biology and Genetics, Bilkent UniversityDepartment of Pathology, Microbiology & Immunology, University of South CarolinaDepartment of Drug Discovery and Biomedical Sciences, University of South CarolinaTranslational Research Department, Institut Curie, PSL Research UniversityDepartment of Pathology, Faculty of Medicine, Hacettepe UniversityDepartment of Medical Oncology, Hacettepe University Cancer InstituteDepartment of Pathology, Faculty of Medicine, Hacettepe UniversityTranslational Research Department, Institut Curie, PSL Research UniversityDepartment of Drug Discovery and Biomedical Sciences, University of South CarolinaDepartment of Biochemistry and Molecular Biology, Hollings Cancer Center, Medical University of South CarolinaAbstract 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.https://doi.org/10.1038/s41467-023-42736-y |
| spellingShingle | 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 Ozgur Sahin Toxic PARP trapping upon cAMP-induced DNA damage reinstates the efficacy of endocrine therapy and CDK4/6 inhibitors in treatment-refractory ER+ breast cancer Nature Communications |
| title | Toxic PARP trapping upon cAMP-induced DNA damage reinstates the efficacy of endocrine therapy and CDK4/6 inhibitors in treatment-refractory ER+ breast cancer |
| title_full | Toxic PARP trapping upon cAMP-induced DNA damage reinstates the efficacy of endocrine therapy and CDK4/6 inhibitors in treatment-refractory ER+ breast cancer |
| title_fullStr | Toxic PARP trapping upon cAMP-induced DNA damage reinstates the efficacy of endocrine therapy and CDK4/6 inhibitors in treatment-refractory ER+ breast cancer |
| title_full_unstemmed | Toxic PARP trapping upon cAMP-induced DNA damage reinstates the efficacy of endocrine therapy and CDK4/6 inhibitors in treatment-refractory ER+ breast cancer |
| title_short | Toxic PARP trapping upon cAMP-induced DNA damage reinstates the efficacy of endocrine therapy and CDK4/6 inhibitors in treatment-refractory ER+ breast cancer |
| title_sort | toxic parp trapping upon camp induced dna damage reinstates the efficacy of endocrine therapy and cdk4 6 inhibitors in treatment refractory er breast cancer |
| url | https://doi.org/10.1038/s41467-023-42736-y |
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