PXD036614-2

PXD036614 is an original dataset announced via ProteomeXchange.

Title	Multi-omic profiling of breast cancer cells uncovers stress MAPK-associated sensitivity to AKT degradation
Description	Over 50% of human tumors display hyperactivation of the serine/threonine kinase AKT, but AKT inhibitors under clinical investigation lack therapeutic efficacy at tolerable doses and display significant on-target toxicities. Here we report the development of a second-generation AKT degrader, INY-05-040, which outperformed catalytic AKT inhibition both with respect to biochemical and cellular suppression of AKT-driven phenotypes in breast cancer cell lines. A systematic growth inhibition screen across 288 cancer cell lines confirmed a substantially higher potency for INY-05-040 (median GI50adj = 1.1 µM) compared to our first-generation AKT degrader (INY-03-041; median GI50adj = 3.1 µM), with both compounds outperforming catalytic AKT inhibition with GDC-0068 (median GI50adj > 10 µM). Using multi-omic profiling and causal network integration in breast cancer cells, we demonstrate that the enhanced efficacy of INY-05-040 is associated with sustained suppression of AKT signaling, followed by a potent induction of the stress mitogen activated protein kinase (MAPK) cJun N-terminal kinase (JNK). Further integration of growth inhibition assays with publicly available transcriptomic, proteomic, and reverse phase protein array (RPPA) measurements established low baseline JNK signaling as a biomarker for breast cancer sensitivity to AKT degradation. Collectively, our study presents a systematic framework for mapping the network-wide signaling effects of therapeutically relevant compounds, revealing that INY-05-040 is a potent pharmacological suppressor of AKT signaling.
HostingRepository	PRIDE
AnnounceDate	2024-10-22
AnnouncementXML	Submission_2024-10-22_06:31:44.846.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Eric Fischer
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	TMT6plex-126 reporter+balance reagent acylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2022-09-12 03:41:10	ID requested
1	2024-02-28 02:36:23	announced
⏵ 2	2024-10-22 06:31:45	announced	2024-10-22: Updated project metadata.

Dataset with its publication pending

submitter keyword: cancer, AKT, network biology,degrader, PI3K signaling

Eric Fischer
contact affiliation	Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA., Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA
contact email	eric_fischer@dfci.harvard.edu
lab head
Eric Fischer
contact affiliation	Dana-Farber Cancer Institute
contact email	eric_fischer@dfci.harvard.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD036614
     1. Label: PRIDE project
     2. Name: Multi-omic profiling of breast cancer cells uncovers stress MAPK-associated sensitivity to AKT degradation