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dc.contributor.authorJaaks, Patricia
dc.contributor.authorCoker, Elizabeth A
dc.contributor.authorVis, Daniel J
dc.contributor.authorEdwards, Olivia
dc.contributor.authorCarpenter, Emma
dc.contributor.authorLeto, Simonetta M
dc.contributor.authorDwane, Lisa
dc.contributor.authorSassi, Francesco
dc.contributor.authorLightfoot, Howard
dc.contributor.authorBarthorpe, Syd
dc.contributor.authorvan der Meer, Dieudonne
dc.contributor.authorYang, Wanjuan
dc.contributor.authorBeck, Alexandra
dc.contributor.authorMironenko, Tatiana
dc.contributor.authorHall, Caitlin
dc.contributor.authorHall, James
dc.contributor.authorMali, Iman
dc.contributor.authorRichardson, Laura
dc.contributor.authorTolley, Charlotte
dc.contributor.authorMorris, James
dc.contributor.authorThomas, Frances
dc.contributor.authorLleshi, Ermira
dc.contributor.authorAben, Nanne
dc.contributor.authorBenes, Cyril H
dc.contributor.authorBertotti, Andrea
dc.contributor.authorTrusolino, Livio
dc.contributor.authorWessels, Lodewyk
dc.contributor.authorGarnett, Mathew J
dc.date.accessioned2022-04-14T23:30:51Z
dc.date.available2022-04-14T23:30:51Z
dc.date.issued2022-03
dc.identifier.issn0028-0836
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/336120
dc.description.abstractCombinations of anti-cancer drugs can overcome resistance and provide new treatments1,2. The number of possible drug combinations vastly exceeds what could be tested clinically. Efforts to systematically identify active combinations and the tissues and molecular contexts in which they are most effective could accelerate the development of combination treatments. Here we evaluate the potency and efficacy of 2,025 clinically relevant two-drug combinations, generating a dataset encompassing 125 molecularly characterized breast, colorectal and pancreatic cancer cell lines. We show that synergy between drugs is rare and highly context-dependent, and that combinations of targeted agents are most likely to be synergistic. We incorporate multi-omic molecular features to identify combination biomarkers and specify synergistic drug combinations and their active contexts, including in basal-like breast cancer, and microsatellite-stable or KRAS-mutant colon cancer. Our results show that irinotecan and CHEK1 inhibition have synergistic effects in microsatellite-stable or KRAS-TP53 double-mutant colon cancer cells, leading to apoptosis and suppression of tumour xenograft growth. This study identifies clinically relevant effective drug combinations in distinct molecular subpopulations and is a resource to guide rational efforts to develop combinatorial drug treatments.
dc.format.mediumPrint-Electronic
dc.publisherSpringer Science and Business Media LLC
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.titleEffective drug combinations in breast, colon and pancreatic cancer cells.
dc.typeArticle
dc.publisher.departmentWellcome Sanger Institute Student
dc.publisher.departmentDepartment of Medicine
dc.date.updated2022-04-14T10:53:40Z
prism.endingPage173
prism.issueIdentifier7899
prism.numberPMID 33500573
prism.publicationDate2022
prism.publicationNameNature
prism.startingPage166
prism.volume603
dc.identifier.doi10.17863/CAM.83545
dcterms.dateAccepted2022-01-18
rioxxterms.versionofrecord10.1038/s41586-022-04437-2
rioxxterms.versionVoR
dc.contributor.orcidEdwards, Olivia [0000-0001-8753-9348]
dc.contributor.orcidCarpenter, Emma [0000-0002-1911-6842]
dc.contributor.orcidLeto, Simonetta M [0000-0001-7580-6584]
dc.contributor.orcidHall, Caitlin [0000-0002-5713-5980]
dc.contributor.orcidHall, James [0000-0002-8124-5434]
dc.contributor.orcidRichardson, Laura [0000-0002-8075-3816]
dc.contributor.orcidTolley, Charlotte [0000-0002-1119-7983]
dc.contributor.orcidThomas, Frances [0000-0003-2345-0912]
dc.contributor.orcidTrusolino, Livio [0000-0002-6379-3365]
dc.contributor.orcidWessels, Lodewyk [0000-0002-1656-6995]
dc.contributor.orcidGarnett, Mathew J [0000-0002-2618-4237]
dc.identifier.eissn1476-4687
rioxxterms.typeJournal Article/Review
cam.issuedOnline2022-02-23
cam.depositDate2022-04-14
pubs.licence-identifierapollo-deposit-licence-2-1
pubs.licence-display-nameApollo Repository Deposit Licence Agreement


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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International