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AKT Degradation Selectively Inhibits the Growth of PI3K/PTEN Pathway-Mutant Cancers with Wild-Type KRAS and BRAF by Destabilizing Aurora Kinase B
Cancer Discovery ( IF 29.7 ) Pub Date : 2021-12-01 , DOI: 10.1158/2159-8290.cd-20-0815
Jia Xu 1, 2 , Xufen Yu 2, 3, 4 , Tiphaine C Martin 1, 2 , Ankita Bansal 1, 2 , Kakit Cheung 1, 2 , Abigail Lubin 1, 2 , Elias Stratikopoulos 1, 2 , Kaitlyn M Cahuzac 1, 2 , Li Wang 5 , Ling Xie 5 , Royce Zhou 1, 2 , Yudao Shen 2, 3, 4 , Xuewei Wu 1, 2 , Shen Yao 1, 2 , Ruifang Qiao 1, 2 , Poulikos I Poulikakos 1, 2 , Xian Chen 5 , Jing Liu 2, 3, 4 , Jian Jin 1, 2, 3, 4 , Ramon Parsons 1, 2
Affiliation  

Using a panel of cancer cell lines, we characterized a novel degrader of AKT, MS21. In mutant PI3K–PTEN pathway cell lines, AKT degradation was superior to AKT kinase inhibition for reducing cell growth and sustaining lower signaling over many days. AKT degradation, but not kinase inhibition, profoundly lowered Aurora kinase B (AURKB) protein, which is known to be essential for cell division, and induced G2–M arrest and hyperploidy. PI3K activated AKT phosphorylation of AURKB on threonine 73, which protected it from proteasome degradation. A mutant of AURKB (T73E) that mimics phosphorylation and blocks degradation rescued cells from growth inhibition. Degrader-resistant lines were associated with low AKT phosphorylation, wild-type PI3K/PTEN status, and mutation of KRAS/BRAF. Pan-cancer analysis identified that 19% of cases have PI3K–PTEN pathway mutation without RAS pathway mutation, suggesting that these patients with cancer could benefit from AKT degrader therapy that leads to loss of AURKB. Significance: MS21 depletes cells of phosphorylated AKT (pAKT) and a newly identified AKT substrate, AURKB, to inhibit tumor growth in mice. MS21 is superior to prior agents that target PI3K and AKT due to its ability to selectively target active, pAKT and sustain repression of signaling to deplete AURKB. This article is highlighted in the In This Issue feature, [p. 2945][1] [1]: /lookup/volpage/11/2945?iss=12

中文翻译:


AKT 降解通过破坏 Aurora 激酶 B 的稳定性,选择性抑制野生型 KRAS 和 BRAF 的 PI3K/PTEN 通路突变癌症的生长



使用一组癌细胞系,我们鉴定了一种新型 AKT 降解剂 MS21。在突变 PI3K-PTEN 通路细胞系中,AKT 降解优于 AKT 激酶抑制,可减少细胞生长并在多天内维持较低的信号传导。 AKT 降解(而非激酶抑制)显着降低了极光激酶 B (AURKB) 蛋白(已知该蛋白对于细胞分裂至关重要),并诱导 G2-M 期停滞和超倍体。 PI3K 激活苏氨酸 73 上 AURKB 的 AKT 磷酸化,从而保护其免受蛋白酶体降解。 AURKB (T73E) 的突变体模拟磷酸化并阻止降解,使细胞免受生长抑制。降解剂抗性株系与低 AKT 磷酸化、野生型 PI3K/PTEN 状态和 KRAS/BRAF 突变相关。泛癌分析发现,19% 的病例存在 PI3K-PTEN 通路突变,而没有 RAS 通路突变,这表明这些癌症患者可以从导致 AURKB 丢失的 AKT 降解剂治疗中受益。意义:MS21 消耗细胞中的磷酸化 AKT (pAKT) 和新鉴定的 AKT 底物 AURKB,从而抑制小鼠肿瘤生长。 MS21 优于先前靶向 PI3K 和 AKT 的药物,因为它能够选择性地靶向活性 pAKT 并持续抑制信号传导以消耗 AURKB。本文在本期专题中突出显示,[p. 11]。 2945][1][1]:/lookup/volpage/11/2945?iss=12
更新日期:2021-12-02
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