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

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Hyperactivation of the serine/threonine kinase AKT is prevalent in over 50% of human tumors.
• Current AKT inhibitors have limitations in their therapeutic window.
• There is a need for improved therapeutic strategies targeting AKT signaling.

Purpose of the Study:

• To develop and evaluate a second-generation AKT degrader, INY-05-040.
• To compare the efficacy of INY-05-040 against catalytic AKT inhibition and first-generation degraders.
• To identify biomarkers for sensitivity to AKT degradation therapy.

Main Methods:

• Conducted growth inhibition screens across 288 cancer cell lines.
• Utilized multiomic profiling and causal network integration in breast cancer cells.
• Integrated growth inhibition data with public transcriptomic, proteomic, and RPPA datasets.

Main Results:

• INY-05-040 demonstrated superior cellular suppression of AKT-dependent phenotypes compared to catalytic AKT inhibitors.
• INY-05-040 showed substantially higher potency than the first-generation AKT degrader INY-03-041.
• Sustained AKT signaling suppression by INY-05-040 led to c-Jun N-terminal kinase (JNK) induction.
• Low basal JNK signaling was identified as a biomarker for breast cancer sensitivity to AKT degradation.

Conclusions:

• INY-05-040 is a potent pharmacological suppressor of AKT signaling with enhanced efficacy.
• The study provides a framework for mapping network-wide signaling effects of therapeutic compounds.
• Low JNK signaling predicts sensitivity to AKT degradation, offering a potential biomarker for patient selection.