IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v14y2023i1d10.1038_s41467-023-42736-y.html
   My bibliography  Save this article

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

Author

Listed:
  • Ozge Saatci

    (Hollings Cancer Center, Medical University of South Carolina
    University of South Carolina)

  • Metin Cetin

    (Hollings Cancer Center, Medical University of South Carolina
    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
    University of South Carolina)

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.

Suggested Citation

  • 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 S, 2023. "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, Nature, vol. 14(1), pages 1-20, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-42736-y
    DOI: 10.1038/s41467-023-42736-y
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-023-42736-y
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-023-42736-y?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Elodie Montaudon & Joanna Nikitorowicz-Buniak & Laura Sourd & Ludivine Morisset & Rania El Botty & Léa Huguet & Ahmed Dahmani & Pierre Painsec & Fariba Nemati & Sophie Vacher & Walid Chemlali & Julien, 2020. "PLK1 inhibition exhibits strong anti-tumoral activity in CCND1-driven breast cancer metastases with acquired palbociclib resistance," Nature Communications, Nature, vol. 11(1), pages 1-16, December.
    2. Jordi Barretina & Giordano Caponigro & Nicolas Stransky & Kavitha Venkatesan & Adam A. Margolin & Sungjoon Kim & Christopher J.Wilson & Joseph Lehár & Gregory V. Kryukov & Dmitriy Sonkin & Anupama Red, 2012. "Addendum: The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity," Nature, Nature, vol. 492(7428), pages 290-290, December.
    3. Marcin J. Suskiewicz & Florian Zobel & Tom E. H. Ogden & Pietro Fontana & Antonio Ariza & Ji-Chun Yang & Kang Zhu & Lily Bracken & William J. Hawthorne & Dragana Ahel & David Neuhaus & Ivan Ahel, 2020. "HPF1 completes the PARP active site for DNA damage-induced ADP-ribosylation," Nature, Nature, vol. 579(7800), pages 598-602, March.
    4. Jordi Barretina & Giordano Caponigro & Nicolas Stransky & Kavitha Venkatesan & Adam A. Margolin & Sungjoon Kim & Christopher J. Wilson & Joseph Lehár & Gregory V. Kryukov & Dmitriy Sonkin & Anupama Re, 2012. "The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity," Nature, Nature, vol. 483(7391), pages 603-607, March.
    5. Ozge Saatci & Aysegul Kaymak & Umar Raza & Pelin G. Ersan & Ozge Akbulut & Carolyn E. Banister & Vitali Sikirzhytski & Unal Metin Tokat & Gamze Aykut & Suhail A. Ansari & Hayriye Tatli Dogan & Mehmet , 2020. "Targeting lysyl oxidase (LOX) overcomes chemotherapy resistance in triple negative breast cancer," Nature Communications, Nature, vol. 11(1), pages 1-17, December.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Seungyeul Yoo & Abhilasha Sinha & Dawei Yang & Nasser K. Altorki & Radhika Tandon & Wenhui Wang & Deebly Chavez & Eunjee Lee & Ayushi S. Patel & Takashi Sato & Ranran Kong & Bisen Ding & Eric E. Schad, 2022. "Integrative network analysis of early-stage lung adenocarcinoma identifies aurora kinase inhibition as interceptor of invasion and progression," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    2. Alon Stern & Mariam Fokra & Boris Sarvin & Ahmad Abed Alrahem & Won Dong Lee & Elina Aizenshtein & Nikita Sarvin & Tomer Shlomi, 2023. "Inferring mitochondrial and cytosolic metabolism by coupling isotope tracing and deconvolution," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    3. Yanli Liu & Zhong Wu & Jin Zhou & Dinesh K. A. Ramadurai & Katelyn L. Mortenson & Estrella Aguilera-Jimenez & Yifei Yan & Xiaojun Yang & Alison M. Taylor & Katherine E. Varley & Jason Gertz & Peter S., 2021. "A predominant enhancer co-amplified with the SOX2 oncogene is necessary and sufficient for its expression in squamous cancer," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    4. Sayantani Ghosh Dastidar & Bony Kumar & Bo Lauckner & Damien Parrello & Danielle Perley & Maria Vlasenok & Antariksh Tyagi & Nii Koney-Kwaku Koney & Ata Abbas & Sergei Nechaev, 2023. "Transcriptional responses of cancer cells to heat shock-inducing stimuli involve amplification of robust HSF1 binding," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    5. Sumana Srivatsa & Hesam Montazeri & Gaia Bianco & Mairene Coto-Llerena & Mattia Marinucci & Charlotte K. Y. Ng & Salvatore Piscuoglio & Niko Beerenwinkel, 2022. "Discovery of synthetic lethal interactions from large-scale pan-cancer perturbation screens," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    6. Cemal Erdem & Sean M. Gross & Laura M. Heiser & Marc R. Birtwistle, 2023. "MOBILE pipeline enables identification of context-specific networks and regulatory mechanisms," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    7. Lisa Veghini & Davide Pasini & Rui Fang & Pietro Delfino & Dea Filippini & Christian Neander & Caterina Vicentini & Elena Fiorini & Francesca Lupo & Sabrina L. D’Agosto & Carmine Carbone & Antonio Ago, 2024. "Differential activity of MAPK signalling defines fibroblast subtypes in pancreatic cancer," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    8. Felicity J. Ashcroft & Asimina Bourboula & Nur Mahammad & Efrosini Barbayianni & Astrid J. Feuerherm & Thanh Thuy Nguyen & Daiki Hayashi & Maroula G. Kokotou & Konstantinos Alevizopoulos & Edward A. D, 2025. "Next generation thiazolyl ketone inhibitors of cytosolic phospholipase A2 α for targeted cancer therapy," Nature Communications, Nature, vol. 16(1), pages 1-16, December.
    9. Guidantonio Malagoli Tagliazucchi & Anna J. Wiecek & Eloise Withnell & Maria Secrier, 2023. "Genomic and microenvironmental heterogeneity shaping epithelial-to-mesenchymal trajectories in cancer," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    10. Souleymane Abdoul-Azize & Rihab Hami & Gaetan Riou & Céline Derambure & Camille Charbonnier & Jean-Pierre Vannier & Monica L. Guzman & Pascale Schneider & Olivier Boyer, 2024. "Glucocorticoids paradoxically promote steroid resistance in B cell acute lymphoblastic leukemia through CXCR4/PLC signaling," Nature Communications, Nature, vol. 15(1), pages 1-21, December.
    11. Michael Kugler & Felix J. Metzner & Gregor Witte & Karl-Peter Hopfner & Katja Lammens, 2024. "Phosphorylation-mediated conformational change regulates human SLFN11," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    12. Philip East & Gavin P. Kelly & Dhruva Biswas & Michela Marani & David C. Hancock & Todd Creasy & Kris Sachsenmeier & Charles Swanton & Julian Downward & Sophie de Carné Trécesson, 2022. "RAS oncogenic activity predicts response to chemotherapy and outcome in lung adenocarcinoma," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    13. Caterina Bartolacci & Cristina Andreani & Gonçalo Vale & Stefano Berto & Margherita Melegari & Anna Colleen Crouch & Dodge L. Baluya & George Kemble & Kurt Hodges & Jacqueline Starrett & Katerina Poli, 2022. "Targeting de novo lipogenesis and the Lands cycle induces ferroptosis in KRAS-mutant lung cancer," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    14. Sanju Sinha & Karina Barbosa & Kuoyuan Cheng & Mark D. M. Leiserson & Prashant Jain & Anagha Deshpande & David M. Wilson & Bríd M. Ryan & Ji Luo & Ze’ev A. Ronai & Joo Sang Lee & Aniruddha J. Deshpand, 2021. "A systematic genome-wide mapping of oncogenic mutation selection during CRISPR-Cas9 genome editing," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
    15. Carolin Ector & Christoph Schmal & Jeff Didier & Sébastien De Landtsheer & Anna-Marie Finger & Francesca Müller-Marquardt & Johannes H. Schulte & Thomas Sauter & Ulrich Keilholz & Hanspeter Herzel & A, 2024. "Time-of-day effects of cancer drugs revealed by high-throughput deep phenotyping," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    16. Zheqi Li & Olivia McGinn & Yang Wu & Amir Bahreini & Nolan M. Priedigkeit & Kai Ding & Sayali Onkar & Caleb Lampenfeld & Carol A. Sartorius & Lori Miller & Margaret Rosenzweig & Ofir Cohen & Nikhil Wa, 2022. "ESR1 mutant breast cancers show elevated basal cytokeratins and immune activation," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    17. Bingzhen Chen & Wenjuan Zhai & Lingchen Kong, 2022. "Variable selection and collinearity processing for multivariate data via row-elastic-net regularization," AStA Advances in Statistical Analysis, Springer;German Statistical Society, vol. 106(1), pages 79-96, March.
    18. Hao Wang & R. Alejandro Sica & Gurbakhash Kaur & Phillip M. Galbo & Zhixin Jing & Christopher D. Nishimura & Xiaoxin Ren & Ankit Tanwar & Bijan Etemad-Gilbertson & Britta Will & Deyou Zheng & David Fo, 2024. "TMIGD2 is an orchestrator and therapeutic target on human acute myeloid leukemia stem cells," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    19. Tanaz Sharifnia & Mathias J. Wawer & Amy Goodale & Yenarae Lee & Mariya Kazachkova & Joshua M. Dempster & Sandrine Muller & Joan Levy & Daniel M. Freed & Josh Sommer & Jérémie Kalfon & Francisca Vazqu, 2023. "Mapping the landscape of genetic dependencies in chordoma," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    20. Julia Joung & Paul C. Kirchgatterer & Ankita Singh & Jang H. Cho & Suchita P. Nety & Rebecca C. Larson & Rhiannon K. Macrae & Rebecca Deasy & Yuen-Yi Tseng & Marcela V. Maus & Feng Zhang, 2022. "CRISPR activation screen identifies BCL-2 proteins and B3GNT2 as drivers of cancer resistance to T cell-mediated cytotoxicity," Nature Communications, Nature, vol. 13(1), pages 1-14, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-42736-y. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.