Mechanisms behind resistance to PI3K inhibitor treatment induced by the PIM kinase

Jin H. Song, Neha Singh, Libia A. Luevano, Sathish K.R. Padi, Koichi Okumura, Virginie Olive, Stephen M. Black, Noel A. Warfel, David W. Goodrich, Andrew Kraft

Research output: Contribution to journalArticle

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Abstract

Cancer 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.

Original languageEnglish (US)
Pages (from-to)2710-2721
Number of pages12
JournalMolecular Cancer Therapeutics
Volume17
Issue number12
DOIs
StatePublished - Dec 1 2018

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Phosphatidylinositol 3-Kinases
Phosphotransferases
Antioxidant Response Elements
Pentose Phosphate Pathway
Neoplasms
Ubiquitination
NAD
Oxidation-Reduction
Cell Death
Phenotype
Glucose
Therapeutics
Pharmaceutical Preparations
Proteins

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Mechanisms behind resistance to PI3K inhibitor treatment induced by the PIM kinase. / Song, Jin H.; Singh, Neha; Luevano, Libia A.; Padi, Sathish K.R.; Okumura, Koichi; Olive, Virginie; Black, Stephen M.; Warfel, Noel A.; Goodrich, David W.; Kraft, Andrew.

In: Molecular Cancer Therapeutics, Vol. 17, No. 12, 01.12.2018, p. 2710-2721.

Research output: Contribution to journalArticle

Song, JH, Singh, N, Luevano, LA, Padi, SKR, Okumura, K, Olive, V, Black, SM, Warfel, NA, Goodrich, DW & Kraft, A 2018, 'Mechanisms behind resistance to PI3K inhibitor treatment induced by the PIM kinase', Molecular Cancer Therapeutics, vol. 17, no. 12, pp. 2710-2721. https://doi.org/10.1158/1535-7163.MCT-18-0374
Song, Jin H. ; Singh, Neha ; Luevano, Libia A. ; Padi, Sathish K.R. ; Okumura, Koichi ; Olive, Virginie ; Black, Stephen M. ; Warfel, Noel A. ; Goodrich, David W. ; Kraft, Andrew. / Mechanisms behind resistance to PI3K inhibitor treatment induced by the PIM kinase. In: Molecular Cancer Therapeutics. 2018 ; Vol. 17, No. 12. pp. 2710-2721.
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