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

Using a panel of cancer cell lines, we characterized a novel degrader of AKT, MS21. In mutant PI3K/PTEN pathway 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 cancer patients could benefit from AKT degrader therapy that leads to loss of AURKB.