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dc.contributor.authorSaturno, G
dc.contributor.authorLopes, F
dc.contributor.authorNiculescu-Duvaz, I
dc.contributor.authorNiculescu-Duvaz, D
dc.contributor.authorZambon, A
dc.contributor.authorDavies, L
dc.contributor.authorJohnson, L
dc.contributor.authorPreece, N
dc.contributor.authorLee, R
dc.contributor.authorViros, A
dc.contributor.authorHolovanchuk, D
dc.contributor.authorPedersen, M
dc.contributor.authorMcLeary, R
dc.contributor.authorLorigan, P
dc.contributor.authorDhomen, N
dc.contributor.authorFisher, C
dc.contributor.authorBanerji, U
dc.contributor.authorDean, E
dc.contributor.authorKrebs, MG
dc.contributor.authorGore, M
dc.contributor.authorLarkin, J
dc.contributor.authorMarais, R
dc.contributor.authorSpringer, C
dc.date.accessioned2020-11-17T10:59:19Z
dc.date.issued2021-02
dc.identifier.citationAnnals of oncology : official journal of the European Society for Medical Oncology, 2021, 32 (2), pp. 269 - 278
dc.identifier.issn0923-7534
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/4228
dc.identifier.eissn1569-8041
dc.identifier.doi10.1016/j.annonc.2020.10.483
dc.description.abstractBackground KRAS is mutated in ∼90% of pancreatic ductal adenocarcinomas, ∼35% of colorectal cancers and ∼20% of non-small-cell lung cancers. There has been recent progress in targeting G12C KRAS specifically, but therapeutic options for other mutant forms of KRAS are limited, largely because the complexity of downstream signaling and feedback mechanisms mean that targeting individual pathway components is ineffective.Design The protein kinases RAF and SRC are validated therapeutic targets in KRAS-mutant pancreatic ductal adenocarcinomas, colorectal cancers and non-small-cell lung cancers and we show that both must be inhibited to block growth of these cancers. We describe CCT3833, a new drug that inhibits both RAF and SRC, which may be effective in KRAS-mutant cancers.Results We show that CCT3833 inhibits RAF and SRC in KRAS-mutant tumors in vitro and in vivo, and that it inhibits tumor growth at well-tolerated doses in mice. CCT3833 has been evaluated in a phase I clinical trial (NCT02437227) and we report here that it significantly prolongs progression-free survival of a patient with a G12V KRAS spindle cell sarcoma who did not respond to a multikinase inhibitor and therefore had limited treatment options.Conclusions New drug CCT3833 elicits significant preclinical therapeutic efficacy in KRAS-mutant colorectal, lung and pancreatic tumor xenografts, demonstrating a treatment option for several areas of unmet clinical need. Based on these preclinical data and the phase I clinical unconfirmed response in a patient with KRAS-mutant spindle cell sarcoma, CCT3833 requires further evaluation in patients with other KRAS-mutant cancers.
dc.formatPrint-Electronic
dc.format.extent269 - 278
dc.languageeng
dc.language.isoeng
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.titleThe paradox-breaking panRAF plus SRC family kinase inhibitor, CCT3833, is effective in mutant KRAS-driven cancers.
dc.typeJournal Article
dcterms.dateAccepted2020-10-18
rioxxterms.versionofrecord10.1016/j.annonc.2020.10.483
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.licenseref.startdate2021-02
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfAnnals of oncology : official journal of the European Society for Medical Oncology
pubs.issue2
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/Clinical Studies
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Clinical Pharmacology – Adaptive Therapy
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.publication-statusAccepted
pubs.volume32
pubs.embargo.termsNot known
icr.researchteamClinical Pharmacology – Adaptive Therapyen_US
dc.contributor.icrauthorBanerji, Udaien


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