Distinct Resistance Mechanisms Arise to Allosteric Vs. ATP-competitive AKT Inhibitors

Overview

Journal Nat Commun

Specialty Biology

Date 2022 Apr 20

PMID 35440108

Authors

Kristin M Zimmerman Savill

Brian B Lee

Jason Oeh

Jie Lin

Eva Lin

Wei-Jen Chung

Amy Young

Wennie Chen

Monika Mis

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

Kui Lin

Affiliations

Soon will be listed here.

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.

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