{"doi":"10.1093/neuonc/noad248","title":"The ERK inhibitor LY3214996 augments anti-PD-1 immunotherapy in preclinical mouse models of BRAFV600E melanoma brain metastasis","abstract":"BACKGROUND: Immune checkpoint inhibitors (ICI) have revolutionized cancer treatment; however, only a subset of patients with brain metastasis (BM) respond to ICI. Activating mutations in the mitogen-activated protein kinase signaling pathway are frequent in BM. The objective of this study was to evaluate whether therapeutic inhibition of extracellular signal-regulated kinase (ERK) can improve the efficacy of ICI for BM. METHODS: We used immunotypical mouse models of BM bearing dual extracranial/intracranial tumors to evaluate the efficacy of single-agent and dual-agent treatment with selective ERK inhibitor LY3214996 (LY321) and anti-programmed death receptor 1 (PD-1) antibody. We verified target inhibition and drug delivery, then investigated treatment effects on T-cell response and tumor-immune microenvironment using high-parameter flow cytometry, multiplex immunoassays, and T-cell receptor profiling. RESULTS: We found that dual treatment with LY321 and anti-PD-1 significantly improved overall survival in 2 BRAFV600E-mutant murine melanoma models but not in KRAS-mutant murine lung adenocarcinoma. We demonstrate that although LY321 has limited blood-brain barrier (BBB) permeability, combined LY321 and anti-PD-1 therapy increases tumor-infiltrating CD8+ effector T cells, broadens the T-cell receptor repertoire in the extracranial tumor, enriches T-cell clones shared by the periphery and brain, and reduces immunosuppressive cytokines and cell populations in tumors. CONCLUSIONS: Despite the limited BBB permeability of LY321, combined LY321 and anti-PD-1 treatment can improve intracranial disease control by amplifying extracranial immune responses, highlighting the role of extracranial tumors in driving intracranial response to treatment. Combined ERK and PD-1 inhibition is a promising therapeutic approach, worthy of further investigation for patients with melanoma BM.","journal":"Neuro-Oncology","year":2023,"id":350652,"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":10,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9617,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":245156,"name":"Consuelo Torrini","orcid":"0000-0003-2743-0839","position":1,"is_corresponding":false},{"id":278082,"name":"Edwin Nieblas‐Bedolla","orcid":"0000-0001-5879-1800","position":2,"is_corresponding":false},{"id":1026129,"name":"Elizabeth J Summers","orcid":null,"position":3,"is_corresponding":false},{"id":830007,"name":"Emily Sullivan","orcid":"0009-0006-3767-7324","position":4,"is_corresponding":false},{"id":1060795,"name":"Britney S. Zhang","orcid":"0009-0005-6221-4009","position":5,"is_corresponding":false},{"id":1095470,"name":"Emily Batchelor","orcid":null,"position":6,"is_corresponding":false},{"id":1026125,"name":"Braxton Marion","orcid":null,"position":7,"is_corresponding":false},{"id":1095056,"name":"Erika Yamazawa","orcid":"0000-0002-3079-2331","position":8,"is_corresponding":false},{"id":651007,"name":"Samuel C. Markson","orcid":"0000-0001-9053-9867","position":9,"is_corresponding":false},{"id":25157,"name":"Hiroaki Wakimoto","orcid":"0000-0001-8225-241X","position":10,"is_corresponding":false},{"id":357044,"name":"Naema Nayyar","orcid":"0000-0003-3436-8404","position":11,"is_corresponding":false},{"id":28994,"name":"Priscilla K. Brastianos","orcid":"0000-0003-4470-8425","position":12,"is_corresponding":false},{"id":829562,"name":"Magali de Sauvage","orcid":"0000-0001-9486-945X","position":0,"is_corresponding":true}],"reference_count":32,"raw_metadata":null,"created_at":"2026-07-19T01:12:37.409066Z","pmid":"38134951","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":[]}