Hypoxia-induced PIM kinase and laminin-activated integrin alpha 6 mediate resistance to PI3K inhibitors in bone-metastatic CRPC
AuthorToth, Rachel K
Tran, Jack D
Muldong, Michelle T
Nollet, Eric A
Schulz, Veronique V
Jensen, Corbin C
Hazlehurst, Lori A
Miranti, Cindy K
Warfel, Noel A
AffiliationUniv Arizona, Canc Ctr, Prostate Canc Grp, Dept Cellular & Mol Med
castration-resistant prostate cancer
cell adhesion-mediated drug resistance (CAM-DR)
integrin alpha 6
MetadataShow full item record
PublisherE-CENTURY PUBLISHING CORP
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.
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).
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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.
NoteOpen access journal
VersionFinal published version
SponsorsNIHUnited 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]
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