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

• Published in: Science signaling 2024-02, Vol.17 (825), p.eadf2670-eadf2670
• Main Authors: Erickson, Emily C, You, Inchul, Perry, Grace, Dugourd, Aurelien, Donovan, Katherine A, Crafter, Claire, Johannes, Jeffrey W, Williamson, Stuart, Moss, Jennifer I, Ros, Susana, Ziegler, Robert E, Barry, Simon T, Fischer, Eric S, Gray, Nathanael S, Madsen, Ralitsa R, Toker, Alex
• Format: Article
• Language: English
• Subjects: AKT protein; Apoptosis; Biomarkers; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Degradation; Female; Humans; JNK Mitogen-Activated Protein Kinases; Kinases; MAP kinase; Mitogen-Activated Protein Kinase Kinases; Mitogen-Activated Protein Kinases; Mitogens; Multiomics; p38 Mitogen-Activated Protein Kinases - metabolism; Proteasomes; Proteomics; Proto-Oncogene Proteins c-akt - metabolism; Tumor cell lines
• ISSN: 1945-0877; 1937-9145; 1937-9145
• DOI: 10.1126/scisignal.adf2670

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