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The ATR Inhibitor AZD6738 Synergizes with Gemcitabine In Vitro and In Vivo to Induce Pancreatic Ductal Adenocarcinoma Regression.

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cam.issuedOnline2018-06-11
dc.contributor.authorWallez, Yann
dc.contributor.authorDunlop, Charles R
dc.contributor.authorJohnson, Timothy Isaac
dc.contributor.authorKoh, Siang-Boon
dc.contributor.authorFornari, Chiara
dc.contributor.authorYates, James WT
dc.contributor.authorBernaldo de Quirós Fernández, Sandra
dc.contributor.authorLau, Alan
dc.contributor.authorRichards, Frances M
dc.contributor.authorJodrell, Duncan I
dc.contributor.orcidWallez, Yann [0000-0001-9654-6187]
dc.contributor.orcidDunlop, Charles R [0000-0002-8194-2598]
dc.contributor.orcidKoh, Siang-Boon [0000-0002-5494-3800]
dc.contributor.orcidRichards, Frances M [0000-0001-7947-7853]
dc.date.accessioned2018-09-11T09:41:28Z
dc.date.available2018-09-11T09:41:28Z
dc.date.issued2018-08
dc.description.abstractPancreatic ductal adenocarcinoma (PDAC) is among the deadliest cancers, and overall survival rates have barely improved over the past five decades. The antimetabolite gemcitabine remains part of the standard of care but shows very limited antitumor efficacy. Ataxia telangiectasia and Rad3-related protein (ATR), the apical kinase of the intra-S-phase DNA damage response, plays a central role in safeguarding cells from replication stress and can therefore limit the efficacy of antimetabolite drug therapies. We investigated the ability of the ATR inhibitor, AZD6738, to prevent the gemcitabine-induced intra-S-phase checkpoint activation and evaluated the antitumor potential of this combination in vitro and in vivo In PDAC cell lines, AZD6738 inhibited gemcitabine-induced Chk1 activation, prevented cell-cycle arrest, and restrained RRM2 accumulation, leading to the strong induction of replication stress markers only with the combination. Moreover, synergistic growth inhibition was identified in a panel of 5 mouse and 7 human PDAC cell lines using both Bliss Independence and Loewe models. In clonogenic assays, the combination abrogated survival at concentrations for which single agents had minor effects. In vivo, AZD6738 in combination with gemcitabine was well tolerated and induced tumor regression in a subcutaneous allograft model of a KrasG12D; Trp53R172H; Pdx-Cre (KPC) mouse cancer cell line, significantly extending survival. Remarkably, the combination also induced regression of a subgroup of KPC autochthonous tumors, which generally do not respond well to conventional chemotherapy. Altogether, our data suggest that AZD6738 in combination with gemcitabine merits evaluation in a clinical trial in patients with PDAC. Mol Cancer Ther; 17(8); 1670-82. ©2018 AACR.
dc.format.mediumPrint-Electronic
dc.identifier.doi10.17863/CAM.27490
dc.identifier.eissn1538-8514
dc.identifier.issn1535-7163
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/280126
dc.languageeng
dc.language.isoeng
dc.publisherAmerican Association for Cancer Research (AACR)
dc.publisher.urlhttp://dx.doi.org/10.1158/1535-7163.mct-18-0010
dc.subjectAdenocarcinoma
dc.subjectAnimals
dc.subjectAntimetabolites, Antineoplastic
dc.subjectCarcinoma, Pancreatic Ductal
dc.subjectDeoxycytidine
dc.subjectHumans
dc.subjectIndoles
dc.subjectMice
dc.subjectMorpholines
dc.subjectPyrimidines
dc.subjectSulfonamides
dc.subjectSulfoxides
dc.subjectGemcitabine
dc.titleThe ATR Inhibitor AZD6738 Synergizes with Gemcitabine In Vitro and In Vivo to Induce Pancreatic Ductal Adenocarcinoma Regression.
dc.typeArticle
dcterms.dateAccepted2018-05-30
prism.endingPage1682
prism.issueIdentifier8
prism.publicationDate2018
prism.publicationNameMol Cancer Ther
prism.startingPage1670
prism.volume17
pubs.funder-project-idCancer Research UK (CB4270)
pubs.funder-project-idCancer Research UK (C14303/A17197)
pubs.funder-project-idPancreatic Cancer UK (FutureLeaders)
pubs.funder-project-idPancreatic Cancer UK (FLF2015_03_Cambridge)
rioxxterms.licenseref.startdate2018-08
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.typeJournal Article/Review
rioxxterms.versionAM
rioxxterms.versionofrecord10.1158/1535-7163.MCT-18-0010

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