biostudies-literaturede Sauvage MATerry and Jean de Gunzburg MGH Research Scholar AwardBreast Cancer Research FoundationNCI NIH HHSNational Institutes of HealthNIH HHSDemetra Fund of the Hellenic Women’s Association889-901https://www.ebi.ac.uk/biostudies/studies/S-EPMC11066918biostudies-literatureUnknown26(5)<h4>Background</h4>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.<h4>Methods</h4>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 respoNeuro-oncologyThe ERK inhibitor LY3214996 augments anti-PD-1 immunotherapy in preclinical mouse models of BRAFV600E melanoma brain metastasis.PMC110669185R01CA227156-02R01 CA227156ELFF-17Batchelor Ede Sauvage MAYamazawa ETorrini CSullivan EWakimoto HZhang BSNieblas-Bedolla ESummers EJMarion BMarkson SCBrastianos PKNayyar NfalseThe ERK inhibitor LY3214996 augments anti-PD-1 immunotherapy in preclinical mouse models of BRAFV600E melanoma brain metastasis.<h4>Background</h4>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.<h4>Methods</h4>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 respo2024-01-01T00:00:00Z2024 May2025-04-04T01:46:07.073Z2025-04-04T01:46:07.073ZS-EPMC110669183813495110.1093/neuonc/noad248