Hypoxia-induced PIM kinase and laminin-activated integrin alpha 6 mediate resistance to PI3K inhibitors in bone-metastatic CRPC
Author
Toth, Rachel KTran, Jack D
Muldong, Michelle T
Nollet, Eric A
Schulz, Veronique V
Jensen, Corbin C
Hazlehurst, Lori A
Corey, Eva
Durden, Donald
Jamieson, Christina
Miranti, Cindy K
Warfel, Noel A
Affiliation
Univ Arizona, Canc Ctr, Prostate Canc Grp, Dept Cellular & Mol MedIssue Date
2019Keywords
Bone metastasisPI3K
PIM kinase
castration-resistant prostate cancer
cell adhesion-mediated drug resistance (CAM-DR)
hypoxia
integrin alpha 6
Metadata
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E-CENTURY PUBLISHING CORPCitation
Toth, 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.Rights
AJCEU 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).Collection Information
This 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.Abstract
Bone-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.Note
Open access journalISSN
2330-1910PubMed ID
31511835Version
Final published versionSponsors
NIHUnited 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]Additional Links
http://www.ajceu.us/V7N4.htmlCollections
Except where otherwise noted, this item's license is described as AJCEU 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).
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