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dc.contributor.authorLupo, B
dc.contributor.authorSassi, F
dc.contributor.authorPinnelli, M
dc.contributor.authorGalimi, F
dc.contributor.authorZanella, ER
dc.contributor.authorVurchio, V
dc.contributor.authorMigliardi, G
dc.contributor.authorGagliardi, PA
dc.contributor.authorPuliafito, A
dc.contributor.authorManganaro, D
dc.contributor.authorLuraghi, P
dc.contributor.authorKragh, M
dc.contributor.authorPedersen, MW
dc.contributor.authorHorak, ID
dc.contributor.authorBoccaccio, C
dc.contributor.authorMedico, E
dc.contributor.authorPrimo, L
dc.contributor.authorNichol, D
dc.contributor.authorSpiteri, I
dc.contributor.authorHeide, T
dc.contributor.authorVatsiou, A
dc.contributor.authorGraham, TA
dc.contributor.authorÉlez, E
dc.contributor.authorArgiles, G
dc.contributor.authorNuciforo, P
dc.contributor.authorSottoriva, A
dc.contributor.authorDienstmann, R
dc.contributor.authorPasini, D
dc.contributor.authorGrassi, E
dc.contributor.authorIsella, C
dc.contributor.authorBertotti, A
dc.contributor.authorTrusolino, L
dc.date.accessioned2020-09-17T10:46:10Z
dc.date.issued2020-08-05
dc.identifier.citationScience translational medicine, 2020, 12 (555)
dc.identifier.issn1946-6234
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/4071
dc.identifier.eissn1946-6242
dc.identifier.doi10.1126/scitranslmed.aax8313
dc.description.abstractBlockade of epidermal growth factor receptor (EGFR) causes tumor regression in some patients with metastatic colorectal cancer (mCRC). However, residual disease reservoirs typically remain even after maximal response to therapy, leading to relapse. Using patient-derived xenografts (PDXs), we observed that mCRC cells surviving EGFR inhibition exhibited gene expression patterns similar to those of a quiescent subpopulation of normal intestinal secretory precursors with Paneth cell characteristics. Compared with untreated tumors, these pseudodifferentiated tumor remnants had reduced expression of genes encoding EGFR-activating ligands, enhanced activity of human epidermal growth factor receptor 2 (HER2) and HER3, and persistent signaling along the phosphatidylinositol 3-kinase (PI3K) pathway. Clinically, properties of residual disease cells from the PDX models were detected in lingering tumors of responsive patients and in tumors of individuals who had experienced early recurrence. Mechanistically, residual tumor reprogramming after EGFR neutralization was mediated by inactivation of Yes-associated protein (YAP), a master regulator of intestinal epithelium recovery from injury. In preclinical trials, Pan-HER antibodies minimized residual disease, blunted PI3K signaling, and induced long-term tumor control after treatment discontinuation. We found that tolerance to EGFR inhibition is characterized by inactivation of an intrinsic lineage program that drives both regenerative signaling during intestinal repair and EGFR-dependent tumorigenesis. Thus, our results shed light on CRC lineage plasticity as an adaptive escape mechanism from EGFR-targeted therapy and suggest opportunities to preemptively target residual disease.
dc.formatPrint
dc.languageeng
dc.language.isoeng
dc.publisherAMER ASSOC ADVANCEMENT SCIENCE
dc.rights.urihttps://www.rioxx.net/licenses/all-rights-reserved
dc.titleColorectal cancer residual disease at maximal response to EGFR blockade displays a druggable Paneth cell-like phenotype.
dc.typeJournal Article
dcterms.dateAccepted2020-05-22
rioxxterms.versionofrecord10.1126/scitranslmed.aax8313
rioxxterms.licenseref.urihttps://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2020-08
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfScience translational medicine
pubs.issue555
pubs.notesNot known
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/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Evolutionary Genomics & Modelling
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
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Evolutionary Genomics & Modelling
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.publication-statusPublished
pubs.volume12
pubs.embargo.termsNot known
icr.researchteamEvolutionary Genomics & Modelling
dc.contributor.icrauthorSpiteri Sagastume, Maria
dc.contributor.icrauthorHeide, Timon
dc.contributor.icrauthorGraham, Trevor
dc.contributor.icrauthorSottoriva, Andrea


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