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dc.contributor.authorToth, Rachel K
dc.contributor.authorTran, Jack D
dc.contributor.authorMuldong, Michelle T
dc.contributor.authorNollet, Eric A
dc.contributor.authorSchulz, Veronique V
dc.contributor.authorJensen, Corbin C
dc.contributor.authorHazlehurst, Lori A
dc.contributor.authorCorey, Eva
dc.contributor.authorDurden, Donald
dc.contributor.authorJamieson, Christina
dc.contributor.authorMiranti, Cindy K
dc.contributor.authorWarfel, Noel A
dc.date.accessioned2019-10-10T20:49:26Z
dc.date.available2019-10-10T20:49:26Z
dc.date.issued2019
dc.identifier.citationToth, R. K., Tran, J. D., Muldong, M. T., Nollet, E. A., Schulz, V. V., Jensen, C. C., … Warfel, N. A. (2019). Hypoxia-induced PIM kinase and laminin-activated integrin α6 mediate resistance to PI3K inhibitors in bone-metastatic CRPC. American journal of clinical and experimental urology, 7(4), 297–312.en_US
dc.identifier.issn2330-1910
dc.identifier.pmid31511835
dc.identifier.urihttp://hdl.handle.net/10150/634755
dc.description.abstractBone-metastatic castration-resistant prostate cancer (CRPC) is lethal due to inherent resistance to androgen deprivation therapy, chemotherapy, and targeted therapies. Despite the fact that a majority of CRPC patients (approximately 70%) harbor a constitutively active PI3K survival pathway, targeting the PI3K/mTOR pathway has failed to increase overall survival in clinical trials. Here, we identified two separate and independent survival pathways induced by the bone tumor microenvironment that are hyperactivated in CRPC and confer resistance to PI3K inhibitors. The first pathway involves integrin α6β1-mediated adhesion to laminin and the second involves hypoxia-induced expression of PIM kinases. In vitro and in vivo models demonstrate that these pathways transduce parallel but independent signals that promote survival by reducing oxidative stress and preventing cell death. We further demonstrate that both pathways drive resistance to PI3K inhibitors in PTEN-negative tumors. These results provide preclinical evidence that combined inhibition of integrin α6β1 and PIM kinase in CRPC is required to overcome tumor microenvironment-mediated resistance to PI3K inhibitors in PTEN-negative tumors within the hypoxic and laminin-rich bone microenvironment.en_US
dc.description.sponsorshipNIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [CA154835, P30CA023074]; Accelerate for Success Award from the TRIF initiative at University of Arizona; Van Andel Research Institute; American Cancer SocietyAmerican Cancer Society [RSG-16-159-01-CDD]; Department of defense PCRPUnited States Department of Defense [W81XWH-19-1-0455]; PNW Prostate Cancer SPORE [P50CA09-7186, P01CA163227]en_US
dc.language.isoenen_US
dc.publisherE-CENTURY PUBLISHING CORPen_US
dc.relation.urlhttp://www.ajceu.us/V7N4.htmlen_US
dc.rightsAJCEU Copyright © 2019. This article is licensed under a Creative Commons Attribution Non-Commercial 4.0 International License (https://creativecommons.org/licenses/by-nc/4.0/legalcode).en_US
dc.subjectBone metastasisen_US
dc.subjectPI3Ken_US
dc.subjectPIM kinaseen_US
dc.subjectcastration-resistant prostate canceren_US
dc.subjectcell adhesion-mediated drug resistance (CAM-DR)en_US
dc.subjecthypoxiaen_US
dc.subjectintegrin alpha 6en_US
dc.titleHypoxia-induced PIM kinase and laminin-activated integrin alpha 6 mediate resistance to PI3K inhibitors in bone-metastatic CRPCen_US
dc.typeArticleen_US
dc.contributor.departmentUniv Arizona, Canc Ctr, Prostate Canc Grp, Dept Cellular & Mol Meden_US
dc.identifier.journalAMERICAN JOURNAL OF CLINICAL AND EXPERIMENTAL UROLOGYen_US
dc.description.noteOpen access journalen_US
dc.description.collectioninformationThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.edu.en_US
dc.eprint.versionFinal published versionen_US
dc.source.journaltitleAmerican journal of clinical and experimental urology
refterms.dateFOA2019-10-10T20:49:26Z


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