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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.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.eissn2159-8290en_US
dc.identifier.doi10.1158/2159-8290.cd-20-0187
dc.identifier.doi10.1158/2159-8290.cd-20-0187en_US
dc.description.abstractMost patients with <i>KRAS</i> <sup>G12C</sup>-mutant non-small cell lung cancer (NSCLC) experience clinical benefit from selective KRAS<sup>G12C</sup> inhibition, whereas patients with colorectal cancer bearing the same mutation rarely respond. To investigate the cause of the limited efficacy of KRAS<sup>G12C</sup> inhibitors in colorectal cancer, we examined the effects of AMG510 in <i>KRAS</i> <sup>G12C</sup> colorectal cancer cell lines. Unlike NSCLC cell lines, <i>KRAS</i> <sup>G12C</sup> colorectal cancer models have high basal receptor tyrosine kinase (RTK) activation and are responsive to growth factor stimulation. In colorectal cancer lines, KRAS<sup>G12C</sup> inhibition induces higher phospho-ERK rebound than in NSCLC cells. Although upstream activation of several RTKs interferes with KRAS<sup>G12C</sup> blockade, we identify EGFR signaling as the dominant mechanism of colorectal cancer resistance to KRAS<sup>G12C</sup> inhibitors. The combinatorial targeting of EGFR and KRAS<sup>G12C</sup> is highly effective in colorectal cancer cells and patient-derived organoids and xenografts, suggesting a novel therapeutic strategy to treat patients with <i>KRAS</i> <sup>G12C</sup> colorectal cancer. SIGNIFICANCE: The efficacy of KRAS<sup>G12C</sup> inhibitors in NSCLC and colorectal cancer is lineage-specific. RTK dependency and signaling rebound kinetics are responsible for sensitivity or resistance to KRAS<sup>G12C</sup> inhibition in colorectal cancer. EGFR and KRAS<sup>G12C</sup> should be concomitantly inhibited to overcome resistance to KRAS<sup>G12C</sup> blockade in colorectal tumors.<i>See related commentary by Koleilat and Kwong, p. 1094</i>.<i>This article is highlighted in the In This Issue feature, p. 1079</i>.
dc.formatPrint-Electronic
dc.format.extent1129 - 1139
dc.languageeng
dc.language.isoeng
dc.rights.urihttp://www.rioxx.net/licenses/under-embargo-all-rights-reserved
dc.titleEGFR Blockade Reverts Resistance to KRAS<sup>G12C</sup> Inhibition in Colorectal Cancer.
dc.typeJournal Article
dcterms.dateAccepted2020-04-29
rioxxterms.versionAM
rioxxterms.versionofrecord10.1158/2159-8290.cd-20-0187
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.volume10en_US
pubs.embargo.termsNot known
icr.researchteamGastrointestinal Cancer Biology and Genomics
icr.researchteamGastrointestinal Cancer Biology and Genomicsen_US
dc.contributor.icrauthorValeri, Nicolaen


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