dc.contributor.author | Izquierdo, E | |
dc.contributor.author | Carvalho, DM | |
dc.contributor.author | Mackay, A | |
dc.contributor.author | Temelso, S | |
dc.contributor.author | Boult, JKR | |
dc.contributor.author | Pericoli, G | |
dc.contributor.author | Fernandez, E | |
dc.contributor.author | Das, M | |
dc.contributor.author | Molinari, V | |
dc.contributor.author | Grabovska, Y | |
dc.contributor.author | Rogers, RF | |
dc.contributor.author | Ajmone-Cat, MA | |
dc.contributor.author | Proszek, PZ | |
dc.contributor.author | Stubbs, M | |
dc.contributor.author | Depani, S | |
dc.contributor.author | O'Hare, P | |
dc.contributor.author | Yu, L | |
dc.contributor.author | Roumelioti, G | |
dc.contributor.author | Choudhary, JS | |
dc.contributor.author | Clarke, M | |
dc.contributor.author | Fairchild, AR | |
dc.contributor.author | Jacques, TS | |
dc.contributor.author | Grundy, RG | |
dc.contributor.author | Howell, L | |
dc.contributor.author | Picton, S | |
dc.contributor.author | Adamski, J | |
dc.contributor.author | Wilson, S | |
dc.contributor.author | Gray, JC | |
dc.contributor.author | Zebian, B | |
dc.contributor.author | Marshall, LV | |
dc.contributor.author | Carceller, F | |
dc.contributor.author | Grill, J | |
dc.contributor.author | Vinci, M | |
dc.contributor.author | Robinson, SP | |
dc.contributor.author | Hubank, M | |
dc.contributor.author | Hargrave, D | |
dc.contributor.author | Jones, C | |
dc.coverage.spatial | United States | |
dc.date.accessioned | 2024-04-15T12:16:09Z | |
dc.date.available | 2024-04-15T12:16:09Z | |
dc.date.issued | 2022-03-01 | |
dc.identifier | 2159-8290.CD-20-0930 | |
dc.identifier.citation | Cancer Discovery, 2022, 12 (3), pp. 712 - 729 | |
dc.identifier.issn | 2159-8274 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/6200 | |
dc.identifier.eissn | 2159-8290 | |
dc.identifier.eissn | 2159-8290 | |
dc.identifier.doi | 10.1158/2159-8290.CD-20-0930 | |
dc.identifier.doi | 10.1158/2159-8290.CD-20-0930 | |
dc.description.abstract | UNLABELLED: 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. SIGNIFICANCE: 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. This article is highlighted in the In This Issue feature, p. 587. | |
dc.format | Print | |
dc.format.extent | 712 - 729 | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | AMER ASSOC CANCER RESEARCH | |
dc.relation.ispartof | Cancer Discovery | |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | |
dc.subject | Child | |
dc.subject | Humans | |
dc.subject | Brain Stem Neoplasms | |
dc.subject | Cell Line, Tumor | |
dc.subject | Dasatinib | |
dc.subject | Mitogen-Activated Protein Kinase Kinases | |
dc.subject | Neoplasm Recurrence, Local | |
dc.subject | Prospective Studies | |
dc.subject | Protein Kinase Inhibitors | |
dc.title | DIPG Harbors Alterations Targetable by MEK Inhibitors, with Acquired Resistance Mechanisms Overcome by Combinatorial Inhibition. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2021-10-19 | |
dc.date.updated | 2024-04-11T16:59:05Z | |
rioxxterms.version | VoR | |
rioxxterms.versionofrecord | 10.1158/2159-8290.CD-20-0930 | |
rioxxterms.licenseref.startdate | 2022-03-01 | |
rioxxterms.type | Journal Article/Review | |
pubs.author-url | https://www.ncbi.nlm.nih.gov/pubmed/34737188 | |
pubs.issue | 3 | |
pubs.organisational-group | ICR | |
pubs.organisational-group | ICR/Primary Group | |
pubs.organisational-group | ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | ICR/Primary Group/ICR Divisions/Cancer Therapeutics | |
pubs.organisational-group | ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Glioma Team | |
pubs.organisational-group | ICR/Primary Group/ICR Divisions/Molecular Pathology | |
pubs.organisational-group | ICR/Primary Group/ICR Divisions/Molecular Pathology/Glioma Team | |
pubs.organisational-group | ICR/Primary Group/ICR Divisions/Molecular Pathology/Translational Genomics | |
pubs.organisational-group | ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging | |
pubs.organisational-group | ICR/Primary Group/ICR Divisions/Molecular Pathology/Translational Genomics/Translational Genomics (hon.) | |
pubs.organisational-group | ICR/Students | |
pubs.organisational-group | ICR/Students/PhD and MPhil | |
pubs.organisational-group | ICR/Students/PhD and MPhil/16/17 Starting Cohort | |
pubs.organisational-group | ICR/Students/PhD and MPhil/20/21 Starting Cohort | |
pubs.organisational-group | ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging/Pre-Clinical MRI | |
pubs.organisational-group | ICR/ImmNet | |
pubs.publication-status | Published | |
pubs.publisher-url | http://dx.doi.org/10.1158/2159-8290.cd-20-0930 | |
pubs.volume | 12 | |
icr.researchteam | Glioma Team | |
icr.researchteam | Pre-Clinical MRI | |
icr.researchteam | Prote & Metabolomics Fac | |
dc.contributor.icrauthor | Mackay, Alan | |
dc.contributor.icrauthor | Boult, Jessica | |
dc.contributor.icrauthor | Das, Molina | |
dc.contributor.icrauthor | Grabovska, Yura | |
dc.contributor.icrauthor | Helm, Rebecca | |
dc.contributor.icrauthor | Choudhary, Jyoti | |
dc.contributor.icrauthor | Clarke, Matthew | |
dc.contributor.icrauthor | Robinson, Simon | |
dc.contributor.icrauthor | Jones, Chris | |
icr.provenance | Deposited by Prof Chris Jones on 2024-04-11. Deposit type is initial. No. of files: 1. Files: DIPG Harbors Alterations Targetable by MEK Inhibitors, with Acquired Resistance Mechanisms Overcome by Combinatorial Inhibit.pdf | |