AKT is a serine/threonine kinase that is essential for cellular metabolism and proliferation and is overactive in cancer cells. Small molecule catalytic inhibitors of all three AKT isoforms, as well as selective AKT degraders, have been developed, but the therapeutic efficacy of these compounds remains less than optimal. In particular, existing AKT degraders such as INY-03-041 elicit slow degradation kinetics despite improved potency over catalytic inhibitors. Erickson et al. designed a second-generation AKT degrader called INY-05-040, which rapidly degraded AKT protein and showed sustained reduction of AKT and downstream signaling relative to the first-generation degrader. Consistent with the improved efficacy, treatment with INY-05-040 also decreased cell growth in multiple breast cancer cell lines. Transcriptomic and metabolomic analysis of cells treated with INY-05-040 versus the small molecule inhibitor GDC-0068 revealed similarities in downstream gene and metabolic signatures, but also distinct clusters. To further elucidate these differences, a computational method called COSMOS (Causal Oriented Search of Multi-Omics Space) that integrated the transcriptomic and metabolomic datasets was utilized, revealing that degradation of AKT specifically induces activation of the stress mitogen-activated protein kinases (MAPKs) MAPK8 (JNK1) and MAPK14 (p38α), along with inflammatory signaling. Parallel studies analyzing the responsiveness to INY-05-040 in a panel of 288 cancer cell lines integrated with publicly accessible information from the Cancer Dependency map confirmed the COSMOS analysis, showing a positive correlation between sensitivity to INY-05-040 and JNK1 signaling. The findings from Erickson et al. reveal a potential workflow to identify novel downstream mediators that may distinguish the modes of action between small molecule-mediated inhibition versus degradation.

Original reference: Sci. Signal. https://doi.org/10.1126/scisignal.adf2670 (2024)