Mitochondrial inhibition augments the efficacy of imatinib by resetting the metabolic phenotype of gastrointestinal stromal tumor Journal Article

Authors: Vitiello, G. A.; Medina, B. D.; Zeng, S.; Bowler, T. G.; Zhang, J. Q.; Loo, J. K.; Param, N. J.; Liu, M.; Moral, A. J.; Zhao, J. N.; Rossi, F.; Antonescu, C. R.; Balachandran, V. P.; Cross, J. R.; DeMatteo, R. P.
Article Title: Mitochondrial inhibition augments the efficacy of imatinib by resetting the metabolic phenotype of gastrointestinal stromal tumor
Abstract: Purpose: Imatinib dramatically reduces gastrointestinal stromal tumor (GIST) 18F-FDG uptake, providing an early indicator of treatment response. Despite decreased glucose internalization, many GIST cells persist, suggesting that alternative metabolic pathways are used for survival. The role of mitochondria in imatinib-treated GIST is largely unknown. Experimental Design: We quantified the metabolic activity of several human GIST cell lines. We treated human GIST xenografts and genetically engineered KitV558del/+ mice with the mitochondrial oxidative phosphorylation inhibitor VLX600 in combination with imatinib and analyzed tumor volume, weight, histology, molecular signaling, and cell cycle activity. In vitro assays on human GIST cell lines were also performed. Results: Imatinib therapy decreased glucose uptake and downstream glycolytic activity in GIST-T1 and HG129 cells by approximately half and upregulated mitochondrial enzymes and improved mitochondrial respiratory capacity. Mitochondrial inhibition with VLX600 had a direct antitumor effect in vitro while appearing to promote glycolysis through increased AKT signaling and glucose transporter expression. When combined with imatinib, VLX600 prevented imatinib-induced cell cycle escape and reduced p27 expression, leading to increased apoptosis when compared to imatinib alone. In KitV558del/+ mice, VLX600 alone did not induce tumor cell death, but had a profound antitumor effect when combined with imatinib. Conclusions: Our findings show that imatinib alters the metabolic phenotype of GIST, and this may contribute to imatinib resistance. Our work offers preclinical proof of concept of metabolic targeting as an effective strategy for the treatment of GIST. Clin Cancer Res; 24(4); 972-84. © 2017 AACR.
Journal Title: Clinical Cancer Research
Volume: 24
Issue: 4
ISSN: 1078-0432
Publisher: American Association for Cancer Research  
Date Published: 2018-02-15
Start Page: 972
End Page: 984
Language: English
DOI: 10.1158/1078-0432.ccr-17-2697
PROVIDER: scopus
PMCID: PMC5815929
PUBMED: 29246941
Notes: Nanyi Zhao's listed by the first name Julia on the original publication -- John Alec Moral's first and middle names switched on original publication -- Article -- Export Date: 1 March 2018 -- Source: Scopus
Citation Impact
MSK Authors
  1. Ronald P DeMatteo
    635 DeMatteo
  2. Cristina R Antonescu
    747 Antonescu
  3. Ferdinando Rossi
    23 Rossi
  4. Shan Zeng
    26 Zeng
  5. Justin Robert Cross
    72 Cross
  6. Jennifer Qi Zhang
    20 Zhang
  7. Benjamin Medina
    11 Medina
  8. Jennifer Loo
    13 Loo
  9. Nanyi Zhao
    5 Zhao
  10. John Alec Gaite Moral
    8 Moral
  11. Timothy Geoffrey Bowler
    7 Bowler
  12. Nesteene Joy Param
    6 Param
  13. Mengyuan Liu
    4 Liu