{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T23:55:08Z","timestamp":1792799708226,"version":"4.5.0"},"reference-count":71,"publisher":"American Association for Cancer Research (AACR)","issue":"3","license":[{"start":{"date-parts":[[2022,3,8]],"date-time":"2022-03-08T00:00:00Z","timestamp":1646697600000},"content-version":"vor","delay-in-days":7,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Children with Cancer UK Fellow","award":["16-234"],"award-info":[{"award-number":["16-234"]}],"id":[{"id":"https:\/\/ror.org\/04bac6g30","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":["aacrjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2022,3,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title\/>\n                    <jats:p>The survival of children with diffuse intrinsic pontine glioma (DIPG) remains dismal, with new treatments desperately needed. In a prospective biopsy-stratified clinical trial, we combined detailed molecular profiling and drug screening in newly established patient-derived models in vitro and in vivo. We identified in vitro sensitivity to MEK inhibitors in DIPGs harboring MAPK pathway alterations, but treatment of patient-derived xenograft models and a patient at relapse failed to elicit a significant response. We generated trametinib-resistant clones in a BRAFG469V model through continuous drug exposure and identified acquired mutations in MEK1\/2 with sustained pathway upregulation. These cells showed hallmarks of mesenchymal transition and expression signatures overlapping with inherently trametinib-insensitive patient-derived cells, predicting sensitivity to dasatinib. Combined trametinib and dasatinib showed highly synergistic effects in vitro and on ex vivo brain slices. We highlight the MAPK pathway as a therapeutic target in DIPG and show the importance of parallel resistance modeling and combinatorial treatments for meaningful clinical translation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance:<\/jats:title>\n                    <jats:p>We report alterations in the MAPK pathway in DIPGs to confer initial sensitivity to targeted MEK inhibition. We further identify for the first time the mechanism of resistance to single-agent targeted therapy in these tumors and suggest a novel combinatorial treatment strategy to overcome it in the clinic.<\/jats:p>\n                    <jats:p>This article is highlighted in the In This Issue feature, p. 587<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1158\/2159-8290.cd-20-0930","type":"journal-article","created":{"date-parts":[[2021,11,4]],"date-time":"2021-11-04T21:25:10Z","timestamp":1636061110000},"page":"712-729","update-policy":"https:\/\/doi.org\/10.1158\/crossmark_policy","source":"Crossref","is-referenced-by-count":35,"title":["DIPG Harbors Alterations Targetable by MEK Inhibitors, with Acquired Resistance Mechanisms Overcome by Combinatorial Inhibition"],"prefix":"10.1158","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3054-5832","authenticated-orcid":false,"given":"Elisa","family":"Izquierdo","sequence":"first","affiliation":[{"name":"1Division of 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