Heterogeneity of Metabolic Vulnerability in Imatinib -Resistant Gastrointestinal Stromal Tumor.

Wen-Kuan Huang,Jiwei Gao,Chun-Nan Yeh,Catharina Larsson,Juan Yuan,Shuijie Li,Weng-Onn Lui,Robert Bränström,Ziqing Chen,Hao Shi,Huanhuan L Cui

doi:10.3390/cells9061333

Abstract

Metabolic reprogramming is a hallmark of cancer cells in response to targeted therapy. Decreased glycolytic activity with enhanced mitochondrial respiration secondary to imatinib has been shown in imatinib-sensitive gastrointestional stromal tumors (GIST). However, the role of energy metabolism in imatinib-resistant GIST remains poorly characterized. Here, we investigated the effect of imatinib treatment on glycolysis and oxidative phosphorylation (OXPHOS), as well as the effect of inhibition of these energy metabolisms on cell viability in imatinib-resistant and -sensitive GIST cell lines. We observed that imatinib treatment increased OXPHOS in imatinib-sensitive, but not imatinib-resistant, GIST cells. Imatinib also reduced the expression of mitochondrial biogenesis activators (peroxisome proliferator-activated receptor coactivator-1 alpha (PGC1α), nuclear respiratory factor 2 (NRF2), and mitochondrial transcription factor A (TFAM)) and mitochondrial mass in imatinib-sensitive GIST cells. Lower TFAM levels were also observed in imatinib-sensitive GISTs than in tumors from untreated patients. Using the Seahorse system, we observed bioenergetics diversity among the GIST cell lines. One of the acquired resistant cell lines (GIST 882R) displayed a highly metabolically active phenotype with higher glycolysis and OXPHOS levels compared with the parental GIST 882, while the other resistant cell line (GIST T1R) had a similar basal glycolytic activity but lower mitochondrial respiration than the parental GIST T1. Further functional assays demonstrated that GIST 882R was more vulnerable to glycolysis inhibition than GIST 882, while GIST T1R was more resistant to OXPHOS inhibition than GIST T1. These findings highlight the diverse energy metabolic adaptations in GIST cells that allow them to survive upon imatinib treatment and reveal the potential of targeting the metabolism for GIST therapy.

Highlights

Gastrointestinal stromal tumor (GIST) is a mesenchymal tumor that frequently harbors KIT receptor tyrosine kinase mutations [1]
We examined the effect of imatinib on the mitochondrial respiratory function and mitochondrial biogenesis
Expressions of several oxidative phosphorylation (OXPHOS) proteins were increased in both GIST T1 and 882, while no significant alteration of OXPHOS proteins was observed in GIST T1R and 882R (Figure 1a,b)

Summary

Introduction

Gastrointestinal stromal tumor (GIST) is a mesenchymal tumor that frequently harbors KIT receptor tyrosine kinase mutations [1] The majority of these patients benefit from imatinib treatment; a large proportion of patients develop imatinib resistance within two years [2]. The metabolic adaptation to the toxic effects of targeted drugs has been shown to contribute to drug resistance [4,5,6,7]. In these models, resistant subsets of cancer cells rely on increased mitochondrial function and oxidative phosphorylation (OXPHOS). A metabolic shift toward the Warburg effect has been implicated in anticancer drug resistance [8,9]

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Results

Conclusion