IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v13y2022i1d10.1038_s41467-022-29655-0.html
   My bibliography  Save this article

Distinct resistance mechanisms arise to allosteric vs. ATP-competitive AKT inhibitors

Author

Listed:
  • Kristin M. Zimmerman Savill

    (Genentech Inc.
    Cardinal Health)

  • Brian B. Lee

    (Genentech Inc.)

  • Jason Oeh

    (Genentech Inc.)

  • Jie Lin

    (Genentech Inc.)

  • Eva Lin

    (Genentech Inc.)

  • Wei-Jen Chung

    (Genentech Inc.
    Loxo Oncology at Lilly)

  • Amy Young

    (Genentech Inc.
    Oric Pharmaceutical)

  • Wennie Chen

    (Genentech Inc.)

  • Monika Miś

    (Genentech Inc.)

  • Kathryn Mesh

    (Genentech Inc.)

  • Jeffrey Eastham

    (Genentech Inc.)

  • Florian Gnad

    (Genentech Inc.
    Roche Diagnostics)

  • Zhaoshi Jiang

    (Genentech Inc.
    BioMap, Inc.)

  • Eric W. Stawiski

    (Genentech Inc.
    Genentech Inc.
    PACT Pharma)

  • Benjamin Haley

    (Genentech Inc.)

  • Anneleen Daemen

    (Genentech Inc.
    Oric Pharmaceutical)

  • Xiaojing Wang

    (Genentech Inc.)

  • Hartmut Koeppen

    (Genentech Inc.)

  • Zora Modrusan

    (Proteomics, Lipidomics and NGS, Genentech Inc.)

  • Scott E. Martin

    (Genentech Inc.)

  • Deepak Sampath

    (Genentech Inc.
    Ultragenyx Pharmaceutical, Inc.)

  • Kui Lin

    (Genentech Inc.)

Abstract

The AKT kinases have emerged as promising therapeutic targets in oncology and both allosteric and ATP-competitive AKT inhibitors have entered clinical investigation. However, long-term efficacy of such inhibitors will likely be challenged by the development of resistance. We have established prostate cancer models of acquired resistance to the allosteric inhibitor MK-2206 or the ATP-competitive inhibitor ipatasertib following prolonged exposure. While alterations in AKT are associated with acquired resistance to MK-2206, ipatasertib resistance is driven by rewired compensatory activity of parallel signaling pathways. Importantly, MK-2206 resistance can be overcome by treatment with ipatasertib, while ipatasertib resistance can be reversed by co-treatment with inhibitors of pathways including PIM signaling. These findings demonstrate that distinct resistance mechanisms arise to the two classes of AKT inhibitors and that combination approaches may reverse resistance to ATP-competitive inhibition.

Suggested Citation

  • Kristin M. Zimmerman Savill & Brian B. Lee & Jason Oeh & Jie Lin & Eva Lin & Wei-Jen Chung & Amy Young & Wennie Chen & Monika Miś & Kathryn Mesh & Jeffrey Eastham & Florian Gnad & Zhaoshi Jiang & Eric, 2022. "Distinct resistance mechanisms arise to allosteric vs. ATP-competitive AKT inhibitors," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-29655-0
    DOI: 10.1038/s41467-022-29655-0
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-022-29655-0
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-022-29655-0?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. Peter M. Haverty & Eva Lin & Jenille Tan & Yihong Yu & Billy Lam & Steve Lianoglou & Richard M. Neve & Scott Martin & Jeff Settleman & Robert L. Yauch & Richard Bourgon, 2016. "Reproducible pharmacogenomic profiling of cancer cell line panels," Nature, Nature, vol. 533(7603), pages 333-337, May.
    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. Zhi Zhao & Manuela Zucknick, 2020. "Structured penalized regression for drug sensitivity prediction," Journal of the Royal Statistical Society Series C, Royal Statistical Society, vol. 69(3), pages 525-545, June.

    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:13:y:2022:i:1:d:10.1038_s41467-022-29655-0. 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.