Multiomic profiling of breast cancer cells uncovers stress MAPK-associated sensitivity to AKT degradation

• DOI: 10.1126/scisignal.adf2670
• Publication Date: 2024-02-27T18:58:17Z
• Authors: Emily C. Erickson; Inchul You; Grace Perry; Aurelien Dugourd; Katherine A. Donovan; Claire Crafter; Jeffrey W. Johannes; Stuart Williamson; Jennifer I. Moss; Susana Ros; Robert E. Ziegler; Simon T. Barry; Eric S. Fischer; Nathanael S. Gray; Ralitsa R. Madsen; Alex Toker
• Keywords: Proteomics; Mitogen-Activated Protein Kinase Kinases; 0301 basic medicine; JNK Mitogen-Activated Protein Kinases; 610; Breast Neoplasms; Apoptosis; Multiomics; p38 Mitogen-Activated Protein Kinases; 03 medical and health sciences; Humans; Female; Mitogen-Activated Protein Kinases; Mitogens; Proto-Oncogene Proteins c-akt

More than 50% of human tumors display hyperactivation the serine/threonine kinase AKT. Despite evidence clinical efficacy, therapeutic window current generation AKT inhibitors could be improved. Here, we report development a second-generation degrader, INY-05-040, which outperformed catalytic inhibition with respect to cellular suppression AKT-dependent phenotypes in breast cancer cell lines. A growth screen 288 lines confirmed that INY-05-040 had substantially higher potency our first-generation degrader (INY-03-041), both compounds outperforming by GDC-0068. Using multiomic profiling and causal network integration cells, demonstrated enhanced efficacy was associated sustained signaling, followed induction stress mitogen-activated protein (MAPK) c-Jun N-terminal (JNK). Further assays publicly available transcriptomic, proteomic, reverse phase array (RPPA) measurements established low basal JNK signaling as biomarker for sensitivity degradation. Together, study presents framework mapping network-wide effects therapeutically relevant identifies potent pharmacological suppressor signaling.