Please use this identifier to cite or link to this item: https://ahro.austin.org.au/austinjspui/handle/1/19471
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dc.contributor.authorTutuka, Candani S A-
dc.contributor.authorAndrews, Miles C-
dc.contributor.authorMariadason, John M-
dc.contributor.authorIoannidis, Paul-
dc.contributor.authorHudson, Christopher-
dc.contributor.authorCebon, Jonathan S-
dc.contributor.authorBehren, Andreas-
dc.date2017-06-28-
dc.date.accessioned2018-09-17T01:47:15Z-
dc.date.available2018-09-17T01:47:15Z-
dc.date.issued2017-06-28-
dc.identifier.citationMolecular cancer 2017; 16(1): 112en
dc.identifier.urihttp://ahro.austin.org.au/austinjspui/handle/1/19471-
dc.description.abstractBRAF inhibitors (BRAFi) are standard of care for the treatment of BRAF V600 mutation-driven metastatic melanoma, but can lead to paradoxical activation of the mitogen-activated protein kinase (MAPK) signalling pathway. This can result in the promotion of precancerous lesions and secondary neoplasms, mainly (but not exclusively) associated with pre-existing mutations in RAS genes. We previously reported a patient with synchronous BRAF-mutated metastatic melanoma and BRAF wt /KRAS G12D-metastatic colorectal cancer (CRC), whose CRC relapsed and progressed when treated with the BRAF inhibitor dabrafenib (GSK2118436). We used tissue from the resected CRC metastasis to derive a cell line, LM-COL-1, which directly and reliably mimicked the clinical scenario including paradoxical activation of the MAPK signalling pathway resulting in increased cell proliferation upon dabrafenib treatment. Novel BRAF inhibitors (PLX8394 and PLX7904), dubbed as "paradox breakers", were developed to inhibit V600 mutated oncogenic BRAF without causing paradoxical MAPK pathway activation. In this study we used our LM-COL-1 model alongside multiple other CRC cell lines with varying mutational backgrounds to demonstrate and confirm that the paradox breaker PLX8394 retains on-target inhibition of mutated BRAF V600 without paradoxically promoting MAPK signalling.en
dc.language.isoeng-
dc.subjectBRAFen
dc.subjectColorectal canceren
dc.subjectMAPK pathwayen
dc.subjectMelanomaen
dc.subjectParadoxical activationen
dc.titlePLX8394, a new generation BRAF inhibitor, selectively inhibits BRAF in colonic adenocarcinoma cells and prevents paradoxical MAPK pathway activation.en
dc.typeJournal Articleen
dc.identifier.journaltitleMolecular canceren
dc.identifier.affiliationSchool of Cancer Medicine, La Trobe University, Melbourne, Victoria, Australiaen
dc.identifier.affiliationDepartment of Medicine, University of Melbourne, Parkville, Victoria, Australiaen
dc.identifier.affiliationOlivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australiaen
dc.identifier.affiliationDepartment of Medical Oncology, Austin Health, Heidelberg, Victoria, Australiaen
dc.identifier.doi10.1186/s12943-017-0684-xen
dc.type.contentTexten
dc.identifier.orcid0000-0001-5329-280Xen
dc.identifier.pubmedid28659148-
dc.type.austinLetter-
item.openairecristypehttp://purl.org/coar/resource_type/c_18cf-
item.cerifentitytypePublications-
item.grantfulltextnone-
item.openairetypeJournal Article-
item.languageiso639-1en-
item.fulltextNo Fulltext-
crisitem.author.deptOlivia Newton-John Cancer Research Institute-
crisitem.author.deptOlivia Newton-John Cancer Research Institute-
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