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dc.contributor.authorGeorgiou, Aen_US
dc.contributor.authorStewart, Aen_US
dc.contributor.authorCunningham, Den_US
dc.contributor.authorBanerji, Uen_US
dc.contributor.authorWhittaker, SRen_US
dc.date.accessioned2020-03-24T12:47:06Z
dc.date.issued2020-02-25en_US
dc.identifier.citationMolecular cancer research : MCR, 2020en_US
dc.identifier.issn1541-7786en_US
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/3552
dc.identifier.eissn1557-3125en_US
dc.identifier.doi10.1158/1541-7786.mcr-19-1201en_US
dc.description.abstractThrough the use of an unbiased, genome-scale CRISPR modifier screen, we identified NF1 suppression as a mechanism of resistance to EGFR inhibition in NRAS/KRAS/BRAFV600 -wild-type colorectal cancer cells. Reduced NF1 expression permitted sustained signaling through the MAPK pathway to promote cell proliferation in the presence of EGFR inhibition. Targeting of MEK in combination with EGFR inhibition leads to synergistic antiproliferative activity. Human KRAS/NRAS/BRAFV600 -wild-type colorectal cancer cell lines with NF1 mutations displayed reduced NF1 mRNA or protein expression and were resistant to EGFR blockade by gefitinib or cetuximab. Cooccurring loss-of-function mutations in PTEN were associated with resistance to dual EGFR/MEK inhibition but cotreatment with a PI3K inhibitor further suppressed proliferation. Loss of NF1 may be a useful biomarker to identify patients that are less likely to benefit from single-agent anti-EGFR therapy in colorectal cancer and may direct potential combination strategies. IMPLICATIONS: This study suggests that further clinical validation of NF1 status as predictor of response to anti-EGFR targeting antibodies in patients with colorectal cancer with KRAS/NRAS/BRAFV600 -wild-type tumors is warranted.en_US
dc.formatPrint-Electronicen_US
dc.languageengen_US
dc.language.isoengen_US
dc.rights.urihttp://www.rioxx.net/licenses/under-embargo-all-rights-reserveden_US
dc.titleInactivation of NF1 Promotes Resistance to EGFR Inhibition in KRAS/NRAS/BRAFV600-Wild-Type Colorectal Cancer.en_US
dc.typeJournal Article
dcterms.dateAccepted2020-02-20en_US
rioxxterms.versionofrecord10.1158/1541-7786.mcr-19-1201en_US
rioxxterms.licenseref.startdate2020-02-25en_US
rioxxterms.typeJournal Article/Reviewen_US
dc.relation.isPartOfMolecular cancer research : MCRen_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/Clinical Studies
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Clinical Pharmacology – Adaptive Therapy
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Medicine (RMH Smith Cunningham)
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Medicine (RMH Smith Cunningham)/Medicine (RMH Smith Cunningham) (hon.)
pubs.organisational-group/ICR/Primary Group/Royal Marsden Clinical Units
pubs.publication-statusPublisheden_US
pubs.embargo.termsNot knownen_US
icr.researchteamClinical Pharmacology – Adaptive Therapyen_US
icr.researchteamMedicine (RMH Smith Cunningham)en_US
dc.contributor.icrauthorGeorgiou, Alexandrosen_US
dc.contributor.icrauthorBanerji, Udaien_US
dc.contributor.icrauthorCunningham, Daviden_US


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