{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T02:29:27Z","timestamp":1791512967868,"version":"4.3.4"},"reference-count":33,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2023,12,22]],"date-time":"2023-12-22T00:00:00Z","timestamp":1703203200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/100001006","name":"Breast Cancer Research Foundation","doi-asserted-by":"publisher","award":["ELFF-17"],"award-info":[{"award-number":["ELFF-17"]}],"id":[{"id":"10.13039\/100001006","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Demetra Fund of the Hellenic Women\u2019s Association"},{"name":"Terry and Jean de Gunzburg MGH Research Scholar Award"},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["5R01CA227156-02"],"award-info":[{"award-number":["5R01CA227156-02"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,5,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>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.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>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.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>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\u2013brain 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.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>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.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/neuonc\/noad248","type":"journal-article","created":{"date-parts":[[2023,12,23]],"date-time":"2023-12-23T00:11:26Z","timestamp":1703290286000},"page":"889-901","source":"Crossref","is-referenced-by-count":10,"title":["The ERK inhibitor LY3214996 augments anti-PD-1 immunotherapy in preclinical mouse models of BRAFV600E melanoma brain metastasis"],"prefix":"10.1093","volume":"26","author":[{"given":"Magali A","family":"de Sauvage","sequence":"first","affiliation":[{"name":"Center for Cancer Research, Massachusetts General Hospital , Boston , Massachusetts , USA"},{"name":"University of Utah School of Medicine , Salt Lake City, Utah , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Consuelo","family":"Torrini","sequence":"additional","affiliation":[{"name":"Center for Cancer Research, Massachusetts General Hospital , Boston , Massachusetts , USA"},{"name":"Cancer Program, Broad Institute of MIT and Harvard , Cambridge , Massachusetts , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edwin","family":"Nieblas-Bedolla","sequence":"additional","affiliation":[{"name":"Center for Cancer Research, Massachusetts General Hospital , Boston , Massachusetts , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth J","family":"Summers","sequence":"additional","affiliation":[{"name":"Center for Cancer Research, Massachusetts General Hospital , Boston , Massachusetts , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily","family":"Sullivan","sequence":"additional","affiliation":[{"name":"Center for Cancer Research, Massachusetts General Hospital , Boston , Massachusetts , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Britney S","family":"Zhang","sequence":"additional","affiliation":[{"name":"Center for Cancer Research, Massachusetts General Hospital , Boston , Massachusetts , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily","family":"Batchelor","sequence":"additional","affiliation":[{"name":"Center for Cancer Research, Massachusetts General Hospital , Boston , Massachusetts , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Braxton","family":"Marion","sequence":"additional","affiliation":[{"name":"Center for Cancer Research, Massachusetts General Hospital , Boston , Massachusetts , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erika","family":"Yamazawa","sequence":"additional","affiliation":[{"name":"Center for Cancer Research, Massachusetts General Hospital , Boston , Massachusetts , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel C","family":"Markson","sequence":"additional","affiliation":[{"name":"Department of Immunology, Blavatnik Institute, Harvard Medical School , Boston , Massachusetts , USA"},{"name":"Cancer Program, Broad Institute of MIT and Harvard , Cambridge , Massachusetts , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroaki","family":"Wakimoto","sequence":"additional","affiliation":[{"name":"Center for Cancer Research, Massachusetts General Hospital , Boston , Massachusetts , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3436-8404","authenticated-orcid":false,"given":"Naema","family":"Nayyar","sequence":"additional","affiliation":[{"name":"Center for Cancer Research, Massachusetts General Hospital , Boston , Massachusetts , USA"},{"name":"Cancer Program, Broad Institute of MIT and Harvard , Cambridge , Massachusetts , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Priscilla K","family":"Brastianos","sequence":"additional","affiliation":[{"name":"Center for Cancer Research, Massachusetts General Hospital , Boston , Massachusetts , USA"},{"name":"Cancer Program, Broad Institute of MIT and Harvard , Cambridge , Massachusetts , USA"},{"name":"Division of Hematology\/Oncology, Department of Medicine, Massachusetts General Hospital, Boston , Massachusetts , USA"},{"name":"Division of Neuro-Oncology, Department of Neurology, Massachusetts General Hospital. 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