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

TY - JOUR

T1 - Multiomic profiling of breast cancer cells uncovers stress MAPK-associated sensitivity to AKT degradation

AU - Erickson, Emily C.

AU - You, Inchul

AU - Perry, Grace

AU - Dugourd, Aurelien

AU - Donovan, Katherine A.

AU - Crafter, Claire

AU - Johannes, Jeffrey W.

AU - Williamson, Stuart

AU - Moss, Jennifer I.

AU - Ros, Susana

AU - Ziegler, Robert E.

AU - Barry, Simon T.

AU - Fischer, Eric S.

AU - Gray, Nathanael S.

AU - Madsen, Ralitsa R.

AU - Toker, Alex

PY - 2024/2/27

Y1 - 2024/2/27

N2 - 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.

AB - 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.

U2 - 10.1126/scisignal.adf2670

DO - 10.1126/scisignal.adf2670

M3 - Article

C2 - 38412255

SN - 1937-9145

VL - 17

JO - Science Signaling

JF - Science Signaling

IS - 825

ER -