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dc.contributor.authorArulananda, S
dc.contributor.authorO'Brien, M
dc.contributor.authorEvangelista, M
dc.contributor.authorHarris, TJ
dc.contributor.authorSteinohrt, NS
dc.contributor.authorJenkins, LJ
dc.contributor.authorWalkiewicz, M
dc.contributor.authorO'Donoghue, RJJ
dc.contributor.authorPoh, AR
dc.contributor.authorThapa, B
dc.contributor.authorWilliams, DS
dc.contributor.authorLeong, T
dc.contributor.authorMariadason, JM
dc.contributor.authorLi, X
dc.contributor.authorCebon, J
dc.contributor.authorLee, EF
dc.contributor.authorJohn, T
dc.contributor.authorDouglas Fairlie, W
dc.date.accessioned2020-11-26T23:33:31Z
dc.date.available2020-11-26T23:33:31Z
dc.date.issued2020-10-31
dc.identifierpii: 10.1038/s41420-020-00348-1
dc.identifier.citationArulananda, S., O'Brien, M., Evangelista, M., Harris, T. J., Steinohrt, N. S., Jenkins, L. J., Walkiewicz, M., O'Donoghue, R. J. J., Poh, A. R., Thapa, B., Williams, D. S., Leong, T., Mariadason, J. M., Li, X., Cebon, J., Lee, E. F., John, T. & Douglas Fairlie, W. (2020). BCL-XL is an actionable target for treatment of malignant pleural mesothelioma. CELL DEATH DISCOVERY, 6 (1), https://doi.org/10.1038/s41420-020-00348-1.
dc.identifier.issn2058-7716
dc.identifier.urihttp://hdl.handle.net/11343/252268
dc.description.abstractDespite having one of the lowest survival rates of all cancers, there have been no new approved treatments for malignant pleural mesothelioma (MPM) in over a decade. Standard-of-care treatment relies on Cisplatin plus Pemetrexed chemotherapy. Here, we tested a suite of BH3-mimetic drugs targeting BCL-2 pro-survival proteins of the intrinsic apoptotic pathway. We found BCL-XL is the dominant pro-survival protein in a panel of cell lines in vitro, though potent, synergistic cell killing occurred with MCL-1 co-targeting. This correlates with high-level expression of BCL-XL and MCL-1 in cell lines and a large cohort of patient tumour samples. BCL-XL inhibition combined with Cisplatin also enhanced cell killing. In vivo BCL-XL inhibition was as effective as Cisplatin, and the combination enhanced tumour growth control and survival. Genetic ablation of MCL-1 also enhanced the effects of BCL-XL inhibitors, in vivo. Combined, these data provide a compelling rationale for the clinical investigation of BH3-mimetics targeting BCL-XL in MPM.
dc.languageEnglish
dc.publisherSPRINGERNATURE
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.titleBCL-XL is an actionable target for treatment of malignant pleural mesothelioma
dc.typeJournal Article
dc.identifier.doi10.1038/s41420-020-00348-1
melbourne.affiliation.departmentMedicine and Radiology
melbourne.affiliation.departmentPharmacology and Therapeutics
melbourne.affiliation.departmentMedical Biology (W.E.H.I.)
melbourne.affiliation.departmentClinical Pathology
melbourne.affiliation.departmentAnatomy and Neuroscience
melbourne.source.titleCell Death Discovery
melbourne.source.volume6
melbourne.source.issue1
dc.rights.licenseCC BY
melbourne.elementsid1479530
melbourne.openaccess.pmchttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC7603509
melbourne.contributor.authorMariadason, John
melbourne.contributor.authorWilliams, David
melbourne.contributor.authorLeong, Trishe
melbourne.contributor.authorO'Donoghue, Robert
melbourne.contributor.authorPoh, Ashleigh
melbourne.contributor.authorTHAPA, BIBHUSAL
melbourne.contributor.authorCEBON, JONATHAN
melbourne.contributor.authorLEE, ERINNA
melbourne.contributor.authorJohn, Thomas
dc.identifier.eissn2058-7716
melbourne.accessrightsOpen Access


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