IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v15y2024i1d10.1038_s41467-024-52202-y.html
   My bibliography  Save this article

Targeted transcriptional downregulation of MYC using epigenomic controllers demonstrates antitumor activity in hepatocellular carcinoma models

Author

Listed:
  • William Senapedis

    (Omega Therapeutics)

  • Kayleigh M. Gallagher

    (Omega Therapeutics
    AstraZeneca)

  • Elmer Figueroa

    (Omega Therapeutics
    Flagship Pioneering)

  • Jeremiah D. Farelli

    (Omega Therapeutics)

  • Robert Lyng

    (Omega Therapeutics
    SalioGen Therapeutics)

  • J. Graeme Hodgson

    (Omega Therapeutics)

  • Charles W. O’Donnell

    (Omega Therapeutics)

  • Joseph V. Newman

    (Omega Therapeutics)

  • Madison Pacaro

    (Omega Therapeutics)

  • Stephen K. Siecinski

    (Omega Therapeutics)

  • Justin Chen

    (Omega Therapeutics)

  • Thomas G. McCauley

    (Omega Therapeutics)

Abstract

Dysregulation of master regulator c-MYC (MYC) plays a central role in hepatocellular carcinoma (HCC) and other cancers but remains an elusive target for therapeutic intervention. MYC expression is epigenetically modulated within naturally occurring DNA loop structures, Insulated Genomic Domains (IGDs). We present a therapeutic approach using an epigenomic controller (EC), a programmable epigenomic mRNA medicine, to precisely modify MYC IGD sub-elements, leading to methylation of MYC regulatory elements and durable downregulation of MYC mRNA transcription. Significant antitumor activity is observed in preclinical models of HCC treated with the MYC-targeted EC, as monotherapy or in combination with tyrosine kinase or immune checkpoint inhibitors. These findings pave the way for clinical development of MYC-targeting epigenomic controllers in HCC patients and provide a framework for programmable epigenomic mRNA therapeutics for cancer and other diseases.

Suggested Citation

  • William Senapedis & Kayleigh M. Gallagher & Elmer Figueroa & Jeremiah D. Farelli & Robert Lyng & J. Graeme Hodgson & Charles W. O’Donnell & Joseph V. Newman & Madison Pacaro & Stephen K. Siecinski & J, 2024. "Targeted transcriptional downregulation of MYC using epigenomic controllers demonstrates antitumor activity in hepatocellular carcinoma models," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-52202-y
    DOI: 10.1038/s41467-024-52202-y
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-024-52202-y
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-024-52202-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. Yong Lei & Xiaotian Zhang & Jianzhong Su & Mira Jeong & Michael C. Gundry & Yung-Hsin Huang & Yubin Zhou & Wei Li & Margaret A. Goodell, 2017. "Targeted DNA methylation in vivo using an engineered dCas9-MQ1 fusion protein," Nature Communications, Nature, vol. 8(1), pages 1-10, December.
    2. Lidan Liu & Jannes Ulbrich & Judith Müller & Torsten Wüstefeld & Lukas Aeberhard & Theresia R. Kress & Nathiya Muthalagu & Lukas Rycak & Ramona Rudalska & Roland Moll & Stefan Kempa & Lars Zender & Ma, 2012. "Deregulated MYC expression induces dependence upon AMPK-related kinase 5," Nature, Nature, vol. 483(7391), pages 608-612, March.
    3. Laura Soucek & Jonathan Whitfield & Carla P. Martins & Andrew J. Finch & Daniel J. Murphy & Nicole M. Sodir & Anthony N. Karnezis & Lamorna Brown Swigart & Sergio Nasi & Gerard I. Evan, 2008. "Modelling Myc inhibition as a cancer therapy," Nature, Nature, vol. 455(7213), pages 679-683, October.
    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. Nicole M. Sodir & Luca Pellegrinet & Roderik M. Kortlever & Tania Campos & Yong-Won Kwon & Shinseog Kim & Daniel Garcia & Alessandra Perfetto & Panayiotis Anastasiou & Lamorna Brown Swigart & Mark J. , 2022. "Reversible Myc hypomorphism identifies a key Myc-dependency in early cancer evolution," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    2. Marine Lanfranchi & Sozerko Yandiev & Géraldine Meyer-Dilhet & Salma Ellouze & Martijn Kerkhofs & Raphael Dos Reis & Audrey Garcia & Camille Blondet & Alizée Amar & Anita Kneppers & Hélène Polvèche & , 2024. "The AMPK-related kinase NUAK1 controls cortical axons branching by locally modulating mitochondrial metabolic functions," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    3. Yuri Frosi & Yen-Chu Lin & Jiang Shimin & Siti Radhiah Ramlan & Kelly Hew & Alf Henrik Engman & Anil Pillai & Kit Yeung & Yue Xiang Cheng & Tobias Cornvik & Par Nordlund & Megan Goh & Dilraj Lama & Za, 2022. "Engineering an autonomous VH domain to modulate intracellular pathways and to interrogate the eIF4F complex," Nature Communications, Nature, vol. 13(1), pages 1-22, December.
    4. Sukanya Panja & Mihai Ioan Truica & Christina Y. Yu & Vamshi Saggurthi & Michael W. Craige & Katie Whitehead & Mayra V. Tuiche & Aymen Al-Saadi & Riddhi Vyas & Shridar Ganesan & Suril Gohel & Frederic, 2024. "Mechanism-centric regulatory network identifies NME2 and MYC programs as markers of Enzalutamide resistance in CRPC," Nature Communications, Nature, vol. 15(1), pages 1-24, December.
    5. Laura Curti & Sara Rohban & Nicola Bianchi & Ottavio Croci & Adrian Andronache & Sara Barozzi & Michela Mattioli & Fernanda Ricci & Elena Pastori & Silvia Sberna & Simone Bellotti & Anna Accialini & R, 2024. "CDK12 controls transcription at damaged genes and prevents MYC-induced transcription-replication conflicts," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    6. Dilraj Lama & Thibault Vosselman & Cagla Sahin & Judit Liaño-Pons & Carmine P. Cerrato & Lennart Nilsson & Kaare Teilum & David P. Lane & Michael Landreh & Marie Arsenian Henriksson, 2024. "A druggable conformational switch in the c-MYC transactivation domain," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    7. Jie Liu & Xuehua Zhong, 2024. "Epiallelic variation of non-coding RNA genes and their phenotypic consequences," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    8. Anja Deutzmann & Delaney K. Sullivan & Renumathy Dhanasekaran & Wei Li & Xinyu Chen & Ling Tong & Wadie D. Mahauad-Fernandez & John Bell & Adriane Mosley & Angela N. Koehler & Yulin Li & Dean W. Felsh, 2024. "Nuclear to cytoplasmic transport is a druggable dependency in MYC-driven hepatocellular carcinoma," Nature Communications, Nature, vol. 15(1), pages 1-13, 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:15:y:2024:i:1:d:10.1038_s41467-024-52202-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.