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dc.contributor.authorOo, Zay Yar
dc.contributor.authorStevenson, Alexander J
dc.contributor.authorProctor, Martina
dc.contributor.authorDaignault, Sheena M
dc.contributor.authorWalpole, Sebastian
dc.contributor.authorLanaganl, Catherine
dc.contributor.authorChen, James
dc.contributor.authorSkalamera, Dubravka
dc.contributor.authorSpoerri, Loredana
dc.contributor.authorAinger, Stephen A
dc.contributor.authorSturm, Richard A
dc.contributor.authorHaass, Nikolas K
dc.contributor.authorGabrielli, Brian
dc.date.accessioned2019-06-09T01:37:06Z
dc.date.available2019-06-09T01:37:06Z
dc.date.issued2018
dc.identifier.issn1078-0432
dc.identifier.doi10.1158/1078-0432.CCR-17-2701
dc.identifier.urihttp://hdl.handle.net/10072/383807
dc.description.abstractPurpose: Checkpoint kinase 1 inhibitors (CHEK1i) have single-agent activity in vitro and in vivo. Here, we have investigated the molecular basis of this activity. Experimental Design: We have assessed a panel of melanoma cell lines for their sensitivity to the CHEK1i GNE-323 and GDC-0575 in vitro and in vivo. The effects of these compounds on responses to DNA replication stress were analyzed in the hypersensitive cell lines. Results: A subset of melanoma cell lines is hypersensitive to CHEK1i-induced cell death in vitro, and the drug effectively inhibits tumor growth in vivo. In the hypersensitive cell lines, GNE-323 triggers cell death without cells entering mitosis. CHEK1i treatment triggers strong RPA2 hyperphosphorylation and increased DNA damage in only hypersensitive cells. The increased replication stress was associated with a defective S-phase cell-cycle checkpoint. The number and intensity of pRPA2 Ser4/8 foci in untreated tumors appeared to be a marker of elevated replication stress correlated with sensitivity to CHEK1i. Conclusions: CHEK1i have single-agent activity in a subset of melanomas with elevated endogenous replication stress. CHEK1i treatment strongly increased this replication stress and DNA damage, and this correlated with increased cell death. The level of endogenous replication is marked by the pRPA2Ser4/8 foci in the untreated tumors, and may be a useful marker of replication stress in vivo.
dc.description.peerreviewedYes
dc.languageEnglish
dc.language.isoeng
dc.publisherAMER ASSOC CANCER RESEARCH
dc.relation.ispartofpagefrom2901
dc.relation.ispartofpageto2912
dc.relation.ispartofissue12
dc.relation.ispartofjournalCLINICAL CANCER RESEARCH
dc.relation.ispartofvolume24
dc.subject.fieldofresearchOncology and carcinogenesis
dc.subject.fieldofresearchcode3211
dc.titleEndogenous Replication Stress Marks Melanomas Sensitive to CHEK1 Inhibitors In Vivo
dc.typeJournal article
dc.type.descriptionC1 - Articles
dc.type.codeC - Journal Articles
gro.hasfulltextNo Full Text
gro.griffith.authorGabrielli, Brian


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