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dc.contributor.authorPeck, B
dc.contributor.authorBland, P
dc.contributor.authorMavrommati, I
dc.contributor.authorMuirhead, G
dc.contributor.authorCottom, H
dc.contributor.authorWai, PT
dc.contributor.authorMaguire, SL
dc.contributor.authorBarker, HE
dc.contributor.authorMorrison, E
dc.contributor.authorKriplani, D
dc.contributor.authorYu, L
dc.contributor.authorGibson, A
dc.contributor.authorFalgari, G
dc.contributor.authorBrennan, K
dc.contributor.authorFarnie, G
dc.contributor.authorBuus, R
dc.contributor.authorMarlow, R
dc.contributor.authorNovo, D
dc.contributor.authorKnight, E
dc.contributor.authorGuppy, N
dc.contributor.authorKolarevic, D
dc.contributor.authorSusnjar, S
dc.contributor.authorMilijic, NM
dc.contributor.authorNaidoo, K
dc.contributor.authorGazinska, P
dc.contributor.authorRoxanis, I
dc.contributor.authorPancholi, S
dc.contributor.authorMartin, L-A
dc.contributor.authorHolgersen, EM
dc.contributor.authorCheang, MCU
dc.contributor.authorNoor, F
dc.contributor.authorPostel-Vinay, S
dc.contributor.authorQuinn, G
dc.contributor.authorMcDade, S
dc.contributor.authorKrasny, L
dc.contributor.authorHuang, P
dc.contributor.authorDaley, F
dc.contributor.authorWallberg, F
dc.contributor.authorChoudhary, JS
dc.contributor.authorHaider, S
dc.contributor.authorTutt, AN
dc.contributor.authorNatrajan, R
dc.date.accessioned2021-04-07T13:46:13Z
dc.date.available2021-04-07T13:46:13Z
dc.date.issued2021-01-28
dc.identifier.citationCancer research, 2021en_US
dc.identifier.issn0008-5472
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/4493
dc.identifier.eissn1538-7445en_US
dc.identifier.eissn1538-7445
dc.identifier.doi10.1158/0008-5472.can-20-1822en_US
dc.identifier.doi10.1158/0008-5472.can-20-1822
dc.description.abstractTriple-negative breast cancers (TNBC) are resistant to standard-of-care chemotherapy and lack known targetable driver gene alterations. Identification of novel drivers could aid the discovery of new treatment strategies for this hard-to-treat patient population, yet studies using high-throughput and accurate models to define the functions of driver genes in TNBC to date have been limited. Here, we employed unbiased functional genomics screening of the 200 most frequently mutated genes in breast cancer, using spheroid cultures to model <i>in vivo</i>-like conditions, and identified the histone acetyltransferase CREBBP as a novel tumor suppressor in TNBC. CREBBP protein expression in patient tumor samples was absent in 8% of TNBCs and at a high frequency in other tumors, including squamous lung cancer, where CREBBP-inactivating mutations are common. In TNBC, CREBBP alterations were associated with higher genomic heterogeneity and poorer patient survival and resulted in upregulation and dependency on a FOXM1 proliferative program. Targeting FOXM1-driven proliferation indirectly with clinical CDK4/6 inhibitors (CDK4/6i) selectively impaired growth in spheroids, cell line xenografts, and patient-derived models from multiple tumor types with CREBBP mutations or loss of protein expression. In conclusion, we have identified CREBBP as a novel driver in aggressive TNBC and identified an associated genetic vulnerability in tumor cells with alterations in CREBBP and provide a preclinical rationale for assessing CREBBP alterations as a biomarker of CDK4/6i response in a new patient population. SIGNIFICANCE: This study demonstrates that CREBBP genomic alterations drive aggressive TNBC, lung cancer, and lymphomas and may be selectively treated with clinical CDK4/6 inhibitors.en_US
dc.formatPrint-Electronicen_US
dc.languageengen_US
dc.language.isoengen_US
dc.rights.urihttp://www.rioxx.net/licenses/all-rights-reserveden_US
dc.title3D Functional Genomics Screens Identify CREBBP as a Targetable Driver in Aggressive Triple-Negative Breast Cancer.en_US
dc.typeJournal Article
dcterms.dateAccepted2020-11-25
rioxxterms.versionVoRen_US
rioxxterms.versionofrecord10.1158/0008-5472.can-20-1822en_US
rioxxterms.licenseref.startdate2021-01-28
dc.relation.isPartOfCancer researchen_US
pubs.notesNot knownen_US
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/Breast Cancer Research
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research/Functional Genomics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Genomic Analysis – Clinical Trials
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Functional Genomics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Molecular and Systems Oncology
pubs.publication-statusPublisheden_US
pubs.embargo.termsNot knownen_US
icr.researchteamGenomic Analysis – Clinical Trials
icr.researchteamFunctional Genomics
icr.researchteamMolecular and Systems Oncology
dc.contributor.icrauthorKrasny, Lukasen_US
dc.contributor.icrauthorNatrajan, Rachaelen_US
dc.contributor.icrauthorBuus, Richarden_US
dc.contributor.icrauthorCheang, Chonen_US
dc.contributor.icrauthorHaider, Syeden_US
dc.contributor.icrauthorHuang, Paulen_US
dc.contributor.icrauthorTutt, Andrewen_US


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