Mechanisms Behind Resistance to PI3K Inhibitor Treatment Induced by the PIM Kinase.
AuthorSong, Jin H
Luevano, Libia A
Padi, Sathish K R
Black, Stephen M
Warfel, Noel A
Goodrich, David W
Kraft, Andrew S
AffiliationUniv Arizona, Dept Cellular & Mol Med
Univ Arizona, Ctr Canc
Univ Arizona, Dept Physiol
Univ Arizona, Dept Med
MetadataShow full item record
PublisherAMER ASSOC CANCER RESEARCH
CitationSong, J. H., Singh, N., Luevano, L. A., Padi, S. K., Okumura, K., Olive, V., ... & Kraft, A. S. (2018). Mechanisms behind resistance to PI3K Inhibitor treatment induced by the PIM kinase. Molecular cancer therapeutics, 17(12), 2710-2721.
JournalMOLECULAR CANCER THERAPEUTICS
Rights© 2018 American Association for Cancer Research
Collection InformationThis 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 email@example.com.
AbstractCancer resistance to PI3K inhibitor therapy can be in part mediated by increases in the PIM1 kinase. However, the exact mechanism by which PIM kinase promotes tumor cell resistance is unknown. Our study unveils the pivotal control of redox signaling by PIM kinases as a driver of this resistance mechanism. PIM1 kinase functions to decrease cellular ROS levels by enhancing nuclear factor erythroid 2-related factor 2 (NRF2)/antioxidant response element activity. PIM prevents cell death induced by PI3K-AKT-inhibitory drugs through a noncanonical mechanism of NRF2 ubiquitination and degradation and translational control of NRF2 protein levels through modulation of eIF4B and mTORC1 activity. Importantly, PIM also controls NAD(P)H production by increasing glucose flux through the pentose phosphate shunt decreasing ROS production, and thereby diminishing the cytotoxicity of PI3K-AKT inhibitors. Treatment with PIM kinase inhibitors reverses this resistance phenotype, making tumors increasingly susceptible to small-molecule therapeutics, which block the PI3K-AKT pathway.
Note12 month embargo; published OnlineFirst September 6, 2018
VersionFinal accepted manuscript
SponsorsUniversity of Arizona Cancer Center support grant [NIH P30CA023074]; NIH [R01CA173200]; DOD [W81XWH-12-1-0560]; American Lung Association Award [LCD-504131]
- PIM Kinase Inhibitors Kill Hypoxic Tumor Cells by Reducing Nrf2 Signaling and Increasing Reactive Oxygen Species.
- Authors: Warfel NA, Sainz AG, Song JH, Kraft AS
- Issue date: 2016 Jul
- eIF4B is a convergent target and critical effector of oncogenic Pim and PI3K/Akt/mTOR signaling pathways in Abl transformants.
- Authors: Chen K, Yang J, Li J, Wang X, Chen Y, Huang S, Chen JL
- Issue date: 2016 Mar 1
- [Wogonoside reverses cisplatin resistance in SGC7901/cDDP cells through inhibition of PI3K/Akt/Nrf2/ARE signaling pathway].
- Authors: Wang LJ, Wang SG, Deng TX
- Issue date: 2018 Aug 25
- Elevation of receptor tyrosine kinases by small molecule AKT inhibitors in prostate cancer is mediated by Pim-1.
- Authors: Cen B, Mahajan S, Wang W, Kraft AS
- Issue date: 2013 Jun 1
- Targeting the PIM protein kinases for the treatment of a T-cell acute lymphoblastic leukemia subset.
- Authors: Padi SKR, Luevano LA, An N, Pandey R, Singh N, Song JH, Aster JC, Yu XZ, Mehrotra S, Kraft AS
- Issue date: 2017 May 2