IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v14y2023i1d10.1038_s41467-023-38552-z.html
   My bibliography  Save this article

Dynamic BH3 profiling identifies pro-apoptotic drug combinations for the treatment of malignant pleural mesothelioma

Author

Listed:
  • Danielle S. Potter

    (Dana-Farber Cancer Institute
    Harvard Medical School)

  • Ruochen Du

    (Dana-Farber Cancer Institute
    Harvard Medical School)

  • Stephan R. Bohl

    (Dana-Farber Cancer Institute
    Harvard Medical School)

  • Kin-Hoe Chow

    (Dana-Farber Cancer Institute
    Dana-Farber Cancer Institute)

  • Keith L. Ligon

    (Harvard Medical School
    Dana-Farber Cancer Institute
    Dana-Farber Cancer Institute
    Brigham and Women’s Hospital)

  • Raphael Bueno

    (Harvard Medical School
    Brigham and Women’s Hospital)

  • Anthony Letai

    (Dana-Farber Cancer Institute
    Harvard Medical School)

Abstract

Malignant pleural mesothelioma (MPM) has relatively ineffective first/second-line therapy for advanced disease and only 18% five-year survival for early disease. Drug-induced mitochondrial priming measured by dynamic BH3 profiling identifies efficacious drugs in multiple disease settings. We use high throughput dynamic BH3 profiling (HTDBP) to identify drug combinations that prime primary MPM cells derived from patient tumors, which also prime patient derived xenograft (PDX) models. A navitoclax (BCL-xL/BCL-2/BCL-w antagonist) and AZD8055 (mTORC1/2 inhibitor) combination demonstrates efficacy in vivo in an MPM PDX model, validating HTDBP as an approach to identify efficacious drug combinations. Mechanistic investigation reveals AZD8055 treatment decreases MCL-1 protein levels, increases BIM protein levels, and increases MPM mitochondrial dependence on BCL-xL, which is exploited by navitoclax. Navitoclax treatment increases dependency on MCL-1 and increases BIM protein levels. These findings demonstrate that HTDBP can be used as a functional precision medicine tool to rationally construct combination drug regimens in MPM and other cancers.

Suggested Citation

  • Danielle S. Potter & Ruochen Du & Stephan R. Bohl & Kin-Hoe Chow & Keith L. Ligon & Raphael Bueno & Anthony Letai, 2023. "Dynamic BH3 profiling identifies pro-apoptotic drug combinations for the treatment of malignant pleural mesothelioma," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-38552-z
    DOI: 10.1038/s41467-023-38552-z
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-023-38552-z
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-023-38552-z?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. Valerie A. Fadok & Donna L. Bratton & David M. Rose & Alan Pearson & R. Alan B. Ezekewitz & Peter M. Henson, 2000. "A receptor for phosphatidylserine-specific clearance of apoptotic cells," Nature, Nature, vol. 405(6782), pages 85-90, May.
    2. Camilo Guzmán & Manish Bagga & Amanpreet Kaur & Jukka Westermarck & Daniel Abankwa, 2014. "ColonyArea: An ImageJ Plugin to Automatically Quantify Colony Formation in Clonogenic Assays," PLOS ONE, Public Library of Science, vol. 9(3), pages 1-9, March.
    Full references (including those not matched with items on IDEAS)

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    Cited by:

    1. Liangrui He & Liyang Wang & Xujiang Yu & Yizhang Tang & Zhao Jiang & Guoliang Yang & Zhuang Liu & Wanwan Li, 2024. "Full-course NIR-II imaging-navigated fractionated photodynamic therapy of bladder tumours with X-ray-activated nanotransducers," Nature Communications, Nature, vol. 15(1), pages 1-19, December.

    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. Anthony V Furano & Charlie E Jones & Vipul Periwal & Kathryn E Callahan & Jean-Claude Walser & Pamela R Cook, 2020. "Cryptic genetic variation enhances primate L1 retrotransposon survival by enlarging the functional coiled coil sequence space of ORF1p," PLOS Genetics, Public Library of Science, vol. 16(8), pages 1-19, August.
    2. Bartosz Wiernicki & Sophia Maschalidi & Jonathan Pinney & Sandy Adjemian & Tom Vanden Berghe & Kodi S. Ravichandran & Peter Vandenabeele, 2022. "Cancer cells dying from ferroptosis impede dendritic cell-mediated anti-tumor immunity," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    3. Johanna Lilja & Jasmin Kaivola & James R. W. Conway & Joni Vuorio & Hanna Parkkola & Pekka Roivas & Michal Dibus & Megan R. Chastney & Taru Varila & Guillaume Jacquemet & Emilia Peuhu & Emily Wang & U, 2024. "SHANK3 depletion leads to ERK signalling overdose and cell death in KRAS-mutant cancers," Nature Communications, Nature, vol. 15(1), pages 1-20, 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_s41467-023-38552-z. 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.