{"doi":"10.1101/2022.10.11.511726","title":"Multi-omic profiling of breast cancer cells uncovers stress MAPK-associated sensitivity to AKT degradation","abstract":"Abstract Over 50% of human tumors display hyperactivation of the serine/threonine kinase AKT. Despite evidence of clinical efficacy, there remains scope to improve upon the therapeutic window of the current generation of AKT inhibitors. 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-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 GI50 adj = 1.1 µM) compared to our first-generation AKT degrader (INY-03-041; median GI50 adj = 3.1 µM), with both compounds outperforming catalytic AKT inhibition with GDC-0068 (median GI50 adj > 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) 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 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, and identifies INY-05-040 as a potent pharmacological suppressor of AKT signaling.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2022,"id":302020,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9575,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":852157,"name":"Inchul You","orcid":null,"position":1,"is_corresponding":false},{"id":849874,"name":"Grace E. Perry","orcid":"0000-0002-0404-9237","position":2,"is_corresponding":false},{"id":52617,"name":"Aurelien Dugourd","orcid":"0000-0002-0714-028X","position":3,"is_corresponding":false},{"id":299772,"name":"Katherine A. Donovan","orcid":"0000-0002-8539-5106","position":4,"is_corresponding":false},{"id":993564,"name":"Claire Crafter","orcid":"0000-0001-6566-0868","position":5,"is_corresponding":false},{"id":993565,"name":"Jeffrey W. Johannes","orcid":"0000-0001-7242-6682","position":6,"is_corresponding":false},{"id":290836,"name":"Stuart C. Williamson","orcid":"0000-0002-5209-4796","position":7,"is_corresponding":false},{"id":993566,"name":"Jennifer Moss","orcid":"0000-0003-0923-229X","position":8,"is_corresponding":false},{"id":349827,"name":"Susana R�os","orcid":"0000-0002-5451-1880","position":9,"is_corresponding":false},{"id":993567,"name":"Robert Ziegler","orcid":"0000-0001-9574-8780","position":10,"is_corresponding":false},{"id":250681,"name":"Simon T. Barry","orcid":"0000-0002-8511-0588","position":11,"is_corresponding":false},{"id":262829,"name":"Eric S. Fischer","orcid":"0000-0001-7337-6306","position":12,"is_corresponding":false},{"id":226581,"name":"Nathanael S. Gray","orcid":"0000-0001-5354-7403","position":13,"is_corresponding":false},{"id":993568,"name":"Ralitsa R. Madsen","orcid":"0000-0001-8844-5167","position":14,"is_corresponding":false},{"id":299606,"name":"Alex Toker","orcid":"0000-0003-0723-4419","position":15,"is_corresponding":false},{"id":993563,"name":"Emily C. Erickson","orcid":"0000-0003-3494-2605","position":0,"is_corresponding":true}],"reference_count":62,"raw_metadata":null,"created_at":"2026-07-19T00:32:06.309890Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}