Jia Xu, Ph.D., Instructor - Oncological Sciences at Icahn School of Medicine at Mount Sinai. In this video, he speaks about the AACR 2022 Abstract - LB195 / 8 - AKT degradation selectively inhibits the growth of PI3K/PTEN pathway mutant cancers with wild type KRAS and BRAF by destabilizing Aurora kinase B.
The PI3K/AKT/mTOR signaling network is one of the most often dysregulated pathways in cancer development, and the serine/threonine kinase AKT serves as a critical node in this route, regulating various cellular and physiological processes. Clinical trials have shown that AKT inhibitors that competitively bind the ATP pocket have a tolerable safety profile and better efficacy for malignancies with pathway mutations; nonetheless, many PI3K/AKT pathway mutant tumors remain resistant. PROTACs are a strong targeted protein degradation technology that hijacks the cellular ubiquitin-proteasome system to cause selective polyubiquitination and destruction of target proteins. We constructed and produced a library of novel small-molecule putative degraders that degrade AKT in cells by recruiting either the cereblon (CRBN) or von Hippel-Lindau (VHL) E3 ligases, which have the ability to degrade AKT in cells and reduce downstream signaling to varying degrees. We found a novel VHL-recruiting AKT degrader, MS21, and described it using a panel of 38 cancer cell lines with varying genotypes and tissue origins using thorough structure-activity relationship studies on various linkers, E3 ligase ligands, and AKT binding moieties. Our findings imply that pharmacologically degrading AKT phosphorylated on threonine 308 and serine 473 selectively inhibits the development of tumor cells with HER2, PIK3CA, PTEN, or AKT1 mutations. AKT degradation by MS21 was superior than AKT kinase inhibition in these PI3K/PTEN pathway mutant lines for reducing cell growth and sustaining lower signaling over many days, and decreased tumor cell growth by lowering the level of Aurora Kinase B, which we discovered to be an AKT substrate protein. AKT degradation, but not kinase inhibition, significantly reduced Aurora kinase B (AURKB) protein, which is known to be required for cell division, and caused G2/M arrest and hyperploidy. PI3K induced AKT phosphorylation of AURKB on threonine 73, preventing it from being degraded by the proteasome. AURKB mutant (T73E) that mimics phosphorylation and prevents its degradation protected cells from MS21-induced growth inhibition. Furthermore, resistance to MS21 was linked to low levels of baseline AKT phosphorylation in cells, as well as mutations in either KRAS or BRAF, and resistance to MS21 could be overcome by combining a MEK inhibitor trametinib with MS21, which not only inhibited MEK but also increased AKT phosphorylation and enhanced AKT degradation. A pan-cancer research found that 19% of cases contain PI3K/PTEN pathway mutations but no RAS pathway mutations, implying that these cancer patients could benefit from AKT degrader therapy that results in AURKB loss.