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

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 W. Stawiski, Benjamin Haley, Anneleen Daemen, Xiaojing Wang, Hartmut Koeppen, Zora Modrusan, Scott E. Martin, Deepak Sampath and Kui Lin ()
Additional contact information
Kristin M. Zimmerman Savill: Genentech Inc.
Brian B. Lee: Genentech Inc.
Jason Oeh: Genentech Inc.
Jie Lin: Genentech Inc.
Eva Lin: Genentech Inc.
Wei-Jen Chung: Genentech Inc.
Amy Young: Genentech Inc.
Wennie Chen: Genentech Inc.
Monika Miś: Genentech Inc.
Kathryn Mesh: Genentech Inc.
Jeffrey Eastham: Genentech Inc.
Florian Gnad: Genentech Inc.
Zhaoshi Jiang: Genentech Inc.
Eric W. Stawiski: Genentech Inc.
Benjamin Haley: Genentech Inc.
Anneleen Daemen: Genentech Inc.
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.
Kui Lin: Genentech Inc.

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-29655-0

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