Please use this identifier to cite or link to this item: https://ahro.austin.org.au/austinjspui/handle/1/18069
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dc.contributor.authorYeung, Yvonne-
dc.contributor.authorLau, David K-
dc.contributor.authorChionh, Fiona-
dc.contributor.authorTran, Hoanh-
dc.contributor.authorTse, Janson W T-
dc.contributor.authorWeickhardt, Andrew J-
dc.contributor.authorNikfarjam, Mehrdad-
dc.contributor.authorScott, Andrew M-
dc.contributor.authorTebbutt, Niall C-
dc.contributor.authorMariadason, John M-
dc.date2017-06-14-
dc.date.accessioned2018-07-10T06:34:25Z-
dc.date.available2018-07-10T06:34:25Z-
dc.date.issued2017-09-
dc.identifier.citationMolecular oncology 2017; 11(9): 1130-1142en
dc.identifier.urihttps://ahro.austin.org.au/austinjspui/handle/1/18069-
dc.description.abstractAdvanced biliary tract cancer (BTC) has a poor prognosis and limited treatment options. The PI3K/Akt/mTOR signalling pathway is hyperactivated in a subset of BTCs, and clinical activity of the mTOR inhibitor everolimus has been observed in some patients with BTC. The goal of this study was to identify biomarkers predictive of everolimus response. Twenty BTC cell lines were assessed for everolimus sensitivity with a spectrum of growth inhibitory responses observed. Molecular biomarkers of sensitivity and resistance were identified by interrogation of the activation status of the Ras/MAPK and PI3K/Akt/mTOR pathways. K-Ras mutations and/or amplifications were identified in 45% of cell lines and were associated with resistance to everolimus. Activating mutations in PIK3CA or loss of PTEN was not predictive of everolimus response; however, high basal levels of pAKT were associated with sensitivity, independent of Ras/MAPK pathway activation status. Notably, everolimus inhibited mTOR signalling to a similar extent in sensitive and resistant cell lines, suggesting that relative dependence on the mTOR pathway rather than the magnitude of pathway inhibition determines everolimus response. Consistent with the known limitations of rapalogs, everolimus induced feedback-mediated activation of AKT in BTC cell lines, which could be overcome by cotreatment with an AKT inhibitor or ATP-competitive mTORC1/mTORC2 inhibitors. However, both approaches failed to induce greater apoptosis compared to everolimus, and mTORC1/mTORC2 kinase inhibitors induced compensatory activation of pERK, identifying an inherent limitation of these agents in BTC cell lines. These findings suggest that future trials of everolimus in BTC would benefit from preselecting patients based on their K-Ras and PI3K/mTOR pathway activation status. The study also identifies strategies for enhancing inhibition of the PI3K/mTOR pathway in BTC cell lines.en
dc.language.isoeng-
dc.subjectAKTen
dc.subjectK-Rasen
dc.subjectbiliary tract canceren
dc.subjecteverolimusen
dc.subjectmTORen
dc.titleK-Ras mutation and amplification status is predictive of resistance and high basal pAKT is predictive of sensitivity to everolimus in biliary tract cancer cell lines.en
dc.typeJournal Articleen
dc.identifier.journaltitleMolecular oncologyen
dc.identifier.affiliationOlivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australiaen
dc.identifier.affiliationLudwig Institute for Cancer Research, Austin Health, Heidelberg, Victoria, Australiaen
dc.identifier.affiliationSchool of Cancer Medicine, La Trobe University, Melbourne, Australiaen
dc.identifier.affiliationDepartment of Surgery, Austin Health, The University of Melbourne, Heidelberg, Victoria, Australiaen
dc.identifier.doi10.1002/1878-0261.12078en
dc.type.contentTexten
dc.identifier.orcid0000-0003-4866-276Xen
dc.identifier.orcid0000-0002-6656-295Xen
dc.identifier.pubmedid28544747-
dc.type.austinJournal Article-
local.name.researcherLau, David K
item.openairecristypehttp://purl.org/coar/resource_type/c_18cf-
item.cerifentitytypePublications-
item.fulltextNo Fulltext-
item.grantfulltextnone-
item.languageiso639-1en-
item.openairetypeJournal Article-
crisitem.author.deptOlivia Newton-John Cancer Research Institute-
crisitem.author.deptOlivia Newton-John Cancer Research Institute-
crisitem.author.deptSurgery (University of Melbourne)-
crisitem.author.deptMolecular Imaging and Therapy-
crisitem.author.deptOlivia Newton-John Cancer Research Institute-
crisitem.author.deptMedical Oncology-
crisitem.author.deptOlivia Newton-John Cancer Wellness and Research Centre-
crisitem.author.deptOlivia Newton-John Cancer Research Institute-
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