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

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 (Lead / Corresponding author), Alex Toker (Lead / Corresponding author)

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Abstract

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.
Original languageEnglish
JournalScience Signaling
Volume17
Issue number825
DOIs
Publication statusPublished - 27 Feb 2024

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