Savill Kristin M Zimmerman, Lee Brian B, Oeh Jason, Lin Jie, Lin Eva, Chung Wei-Jen, Young Amy, Chen Wennie, Miś Monika, Mesh Kathryn, Eastham Jeffrey, Gnad Florian, Jiang Zhaoshi, Stawiski Eric W, Haley Benjamin, Daemen Anneleen, Wang Xiaojing, Koeppen Hartmut, Modrusan Zora, Martin Scott E, Sampath Deepak, Lin Kui
Department of Molecular Oncology, Genentech Inc., South San Francisco, CA, USA.
Cardinal Health, Dublin, OH, USA.
Nat Commun. 2022 Apr 19;13(1):2057. doi: 10.1038/s41467-022-29655-0.
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.
AKT激酶已成为肿瘤学中颇具前景的治疗靶点，变构和ATP竞争性AKT抑制剂均已进入临床研究阶段。然而，这类抑制剂的长期疗效可能会受到耐药性发展的挑战。我们建立了在长期暴露后对变构抑制剂MK-2206或ATP竞争性抑制剂ipatasertib产生获得性耐药的前列腺癌模型。虽然AKT的改变与对MK-2206的获得性耐药有关，但ipatasertib耐药是由平行信号通路重新布线的代偿性活性驱动的。重要的是，用ipatasertib治疗可克服MK-2206耐药，而通过与包括PIM信号传导在内的通路抑制剂联合治疗可逆转ipatasertib耐药。这些发现表明，两类AKT抑制剂产生了不同的耐药机制，联合治疗方法可能会逆转对ATP竞争性抑制的耐药性。
