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dc.contributor.authorAmodio, V
dc.contributor.authorYaeger, R
dc.contributor.authorArcella, P
dc.contributor.authorCancelliere, C
dc.contributor.authorLamba, S
dc.contributor.authorLorenzato, A
dc.contributor.authorArena, S
dc.contributor.authorMontone, M
dc.contributor.authorMussolin, B
dc.contributor.authorBian, Y
dc.contributor.authorWhaley, A
dc.contributor.authorPinnelli, M
dc.contributor.authorMurciano-Goroff, YR
dc.contributor.authorVakiani, E
dc.contributor.authorValeri, N
dc.contributor.authorLiao, W-L
dc.contributor.authorBhalkikar, A
dc.contributor.authorThyparambil, S
dc.contributor.authorZhao, H-Y
dc.contributor.authorde Stanchina, E
dc.contributor.authorMarsoni, S
dc.contributor.authorSiena, S
dc.contributor.authorBertotti, A
dc.contributor.authorTrusolino, L
dc.contributor.authorLi, BT
dc.contributor.authorRosen, N
dc.contributor.authorDi Nicolantonio, F
dc.contributor.authorBardelli, A
dc.contributor.authorMisale, S
dc.date.accessioned2021-02-09T11:28:09Z
dc.date.available2021-02-09T11:28:09Z
dc.date.issued2020-08-01
dc.identifier.citationCancer discovery, 2020, 10 (8), pp. 1129 - 1139
dc.identifier.issn2159-8274
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/4342
dc.identifier.eissn2159-8290
dc.identifier.doi10.1158/2159-8290.cd-20-0187
dc.description.abstractMost patients with KRAS G12C-mutant non-small cell lung cancer (NSCLC) experience clinical benefit from selective KRASG12C inhibition, whereas patients with colorectal cancer bearing the same mutation rarely respond. To investigate the cause of the limited efficacy of KRASG12C inhibitors in colorectal cancer, we examined the effects of AMG510 in KRAS G12C colorectal cancer cell lines. Unlike NSCLC cell lines, KRAS G12C colorectal cancer models have high basal receptor tyrosine kinase (RTK) activation and are responsive to growth factor stimulation. In colorectal cancer lines, KRASG12C inhibition induces higher phospho-ERK rebound than in NSCLC cells. Although upstream activation of several RTKs interferes with KRASG12C blockade, we identify EGFR signaling as the dominant mechanism of colorectal cancer resistance to KRASG12C inhibitors. The combinatorial targeting of EGFR and KRASG12C is highly effective in colorectal cancer cells and patient-derived organoids and xenografts, suggesting a novel therapeutic strategy to treat patients with KRAS G12C colorectal cancer. SIGNIFICANCE: The efficacy of KRASG12C inhibitors in NSCLC and colorectal cancer is lineage-specific. RTK dependency and signaling rebound kinetics are responsible for sensitivity or resistance to KRASG12C inhibition in colorectal cancer. EGFR and KRASG12C should be concomitantly inhibited to overcome resistance to KRASG12C blockade in colorectal tumors.See related commentary by Koleilat and Kwong, p. 1094.This article is highlighted in the In This Issue feature, p. 1079.
dc.formatPrint-Electronic
dc.format.extent1129 - 1139
dc.languageeng
dc.language.isoeng
dc.publisherAMER ASSOC CANCER RESEARCH
dc.rights.urihttps://www.rioxx.net/licenses/under-embargo-all-rights-reserved
dc.titleEGFR Blockade Reverts Resistance to KRASG12C Inhibition in Colorectal Cancer.
dc.typeJournal Article
dcterms.dateAccepted2020-04-29
rioxxterms.versionAM
rioxxterms.versionofrecord10.1158/2159-8290.cd-20-0187
rioxxterms.licenseref.urihttps://www.rioxx.net/licenses/under-embargo-all-rights-reserved
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfCancer discovery
pubs.issue8
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/Gastrointestinal Cancer Biology and Genomics
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/Gastrointestinal Cancer Biology and Genomics
pubs.publication-statusPublished
pubs.volume10
pubs.embargo.termsNot known
icr.researchteamGastrointestinal Cancer Biology and Genomics
icr.researchteamGastrointestinal Cancer Biology and Genomics
dc.contributor.icrauthorValeri, Nicola


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