2. Academic Validation
  3. AKT Degradation Selectively Inhibits the Growth of PI3K/PTEN Pathway-Mutant Cancers with Wild-Type KRAS and BRAF by Destabilizing Aurora Kinase B

AKT Degradation Selectively Inhibits the Growth of PI3K/PTEN Pathway-Mutant Cancers with Wild-Type KRAS and BRAF by Destabilizing Aurora Kinase B

  • Cancer Discov. 2021 Dec 1;11(12):3064-3089. 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
Affiliations

Affiliations

  • 1 Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.
  • 2 The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
  • 3 Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.
  • 4 Mount Sinai Center for Therapeutics Discovery, Icahn School of Medicine at Mount Sinai, New York, New York.
  • 5 Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
  • # Contributed equally.
PMID: 34301793 DOI: 10.1158/2159-8290.CD-20-0815
Abstract

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.

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