{"doi":"10.17615/y9hc-s085","title":"Combined CDK4/6 and ERK1/2 Inhibition Enhances Antitumor Activity in NF1-Associated Plexiform Neurofibroma.","abstract":"PURPOSE: Plexiform neurofibromas (PNF) are peripheral nerve sheath tumors that cause significant morbidity in persons with neurofibromatosis type 1 (NF1), yet treatment options remain limited. To identify novel therapeutic targets for PNF, we applied an integrated multi-omic approach to quantitatively profile kinome enrichment in a mouse model that has predicted therapeutic responses in clinical trials for NF1-associated PNF with high fidelity. EXPERIMENTAL DESIGN: Utilizing RNA sequencing combined with chemical proteomic profiling of the functionally enriched kinome using multiplexed inhibitor beads coupled with mass spectrometry, we identified molecular signatures predictive of response to CDK4/6 and RAS/MAPK pathway inhibition in PNF. Informed by these results, we evaluated the efficacy of the CDK4/6 inhibitor, abemaciclib, and the ERK1/2 inhibitor, LY3214996, alone and in combination in reducing PNF tumor burden in Nf1flox/flox;PostnCre mice. RESULTS: Converging signatures of CDK4/6 and RAS/MAPK pathway activation were identified within the transcriptome and kinome that were conserved in both murine and human PNF. We observed robust additivity of the CDK4/6 inhibitor, abemaciclib, in combination with the ERK1/2 inhibitor, LY3214996, in murine and human NF1(Nf1) mutant Schwann cells. Consistent with these findings, the combination of abemaciclib (CDK4/6i) and LY3214996 (ERK1/2i) synergized to suppress molecular signatures of MAPK activation and exhibited enhanced antitumor activity in Nf1flox/flox;PostnCre mice in vivo. CONCLUSIONS: These findings provide rationale for the clinical translation of CDK4/6 inhibitors alone and in combination with therapies targeting the RAS/MAPK pathway for the treatment of PNF and other peripheral nerve sheath tumors in persons with NF1.","journal":"UNC Libraries","year":2025,"id":578473,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9602,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":109197,"name":"D. Wade Clapp","orcid":"0000-0001-9465-0917","position":1,"is_corresponding":false},{"id":314339,"name":"George E. Sandusky","orcid":"0000-0003-0769-057X","position":2,"is_corresponding":false},{"id":1073927,"name":"Gregory P. Donoho","orcid":"0009-0007-8865-5093","position":3,"is_corresponding":false},{"id":391152,"name":"Steven P. Angus","orcid":"0000-0002-7655-657X","position":4,"is_corresponding":false},{"id":301226,"name":"Andrea R. Masters","orcid":"0000-0002-9570-8786","position":5,"is_corresponding":false},{"id":1073924,"name":"Jenna Koenig","orcid":"0000-0001-6952-955X","position":6,"is_corresponding":false},{"id":877333,"name":"Qingbo Lu","orcid":"0009-0005-6786-9100","position":7,"is_corresponding":false},{"id":334696,"name":"Chi Zhang","orcid":"0000-0001-9553-0925","position":8,"is_corresponding":false},{"id":276988,"name":"Pengtao Dang","orcid":"0009-0005-0144-0432","position":9,"is_corresponding":false},{"id":702405,"name":"Dana K. Mitchell","orcid":"0000-0002-1022-1072","position":10,"is_corresponding":false},{"id":592286,"name":"Melinda D. Willard","orcid":"0000-0002-2937-962X","position":11,"is_corresponding":false},{"id":638878,"name":"Jiangang Liu","orcid":"0000-0002-2800-077X","position":12,"is_corresponding":false},{"id":1073925,"name":"Weihua Shen","orcid":"0009-0002-5249-5175","position":13,"is_corresponding":false},{"id":517988,"name":"Waylan Bessler","orcid":"0000-0003-0685-9206","position":14,"is_corresponding":false},{"id":517985,"name":"Steven D. 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Flint","orcid":"0000-0001-5698-9776","position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":null,"created_at":"2026-07-19T02:58:20.638044Z","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":[]}