ArticleCancer discovery2021
AKT Degradation Selectively Inhibits the Growth of PI3K/PTEN Pathway-Mutant Cancers with Wild-Type KRAS and BRAF by Destabilizing Aurora Kinase B.
Article in Cancer discovery, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 40 papers.
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Who cites it
40 citing papers in PubMed, 65 citations in OpenAlex.
- Rewiring KRAS-driven cancers through the ubiquitin-proteasome system: therapeutic opportunities with a focus on deubiquitinase.Experimental & molecular medicine · 2026Review
- A renaissance in targeting the PI3K/AKT/mTOR pathway.Nature reviews. Drug discovery · 2026Review
- Allosteric PROTACs: Expanding the Horizon of Targeted Protein Degradation.Journal of the American Chemical Society · 2026Review
- Bioinformatics analysis identifies AURKB as a prognostic biomarker across multiple human cancers.Discover oncology · 2026Article
- Discovery of the first-in-class Aurora B kinase selective degrader.European journal of medicinal chemistry · 2025Article
- DNA-methylation eraser TET2 activates WTIP expression to suppress an AKT-dependent chemoresistance of gastric cancer.Neoplasia (New York, N.Y.) · 2025Article
- Neobractatin and Trametinib Synergistically Induce Apoptosis and Gasdermin E-Dependent Pyroptosis in Pancreatic Cancer Cells.MedComm · 2025Article
- A proximity-induced chimera platform for targeted protein arginine methylation.Acta pharmaceutica Sinica. B · 2025Article
- Differences between lung adenocarcinoma and lung squamous cell carcinoma: Driver genes, therapeutic targets, and clinical efficacy.Genes & diseases · 2025Review
- Recent advances in targeted degradation in the RAS pathway.Future medicinal chemistry · 2025Review
- A PROTAC degrader suppresses oncogenic functions of PTK6, inducing apoptosis of breast cancer cells.Cell chemical biology · 2025Article
- Proteomic profiling identifies upregulation of aurora kinases causing resistance to taxane-type chemotherapy in triple negative breast cancer.Scientific reports · 2025Article
- Investigation of TSRP reverses imatinib resistance through the PI3K / Akt pathway in chronic myeloid leukemia.Annals of hematology · 2024Article
- AKT kinases as therapeutic targets.Journal of experimental & clinical cancer research : CR · 2024Review
- Immune status and combined immunotherapy progression in Kirsten rat sarcoma viral oncogene homolog (KRAS)-mutant tumors.Chinese journal of cancer research = Chung-kuo yen cheng yen chiu · 2024Article
- The role of proteasomes in tumorigenesis.Genes & diseases · 2024Review
- Article
- Down-regulation of AKT proteins slows the growth of mutant-KRAS pancreatic tumors.bioRxiv : the preprint server for biology · 2024Article
- Taenia solium cysticerci's extracellular vesicles Attenuate the AKT/mTORC1 pathway for Alleviating DSS-induced colitis in a murine model.Journal of extracellular vesicles · 2024Article
- Selectivity Studies and Free Energy Calculations of AKT Inhibitors.Molecules (Basel, Switzerland) · 2024Article
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Authors and funding
20 authors at 2 institutions in 1 country.
Funding
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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