Inhibition of mitochondrial glutaminase activity reverses acquired erlotinib resistance in non-small cell lung cancer

The resurgence of research in cancer metabolism has recently broadened interests beyond glucose and the Warburg Effect to other nutrients including glutamine. Because oncogenic alterations of metabolism render cancer cells addicted to nutrients, pathways involved in glycolysis or glutaminolysis could be exploited for therapeutic purposes. In this Review, we provide an updated overview of glutamine metabolism and its involvement in tumorigenesis in vitro and in vivo, and explore the recent potential applications of basic science discoveries in the clinical setting.

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“…EGFR inhibition GLS inhibition restores sensitivity to the EGFR inhibitor erlotinib in cells which had developed resistance 256 .…”

Section: Oncogenic Change Role In Glutamine Metabolismmentioning

confidence: 99%

Erratum: From Krebs to clinic: glutamine metabolism to cancer therapy

Altman¹,

Stine²,

Dang³

2016

Nat Rev Cancer

223

136

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“…GLS has two isoforms: GLS1 (kidney glutaminase) and GLS2 (liver glutaminase). GLS1 has two splice variants: kidney‐type glutaminase (KGA), and glutaminase C (GAC) . This metabolic transformation is the result of complex interactions between a hypoxic tumor microenvironment and oncogenic mutations, such as epidermal growth factor receptor ( EGFR ), TP53 and Kirsten rat sarcoma viral oncogene ( KRAS ) .…”

Section: Introductionmentioning

confidence: 99%

“…GLS1 has two splice variants: kidney-type glutaminase (KGA), and glutaminase C (GAC). 12 This metabolic transformation is the result of complex interactions between a hypoxic tumor microenvironment and oncogenic mutations, such as epidermal growth factor receptor (EGFR), TP53 and Kirsten rat sarcoma viral oncogene (KRAS). 9,[13][14][15][16] Higher glucose utilization correlates with aggressive tumor behavior and treatment resistance including radiotherapy.…”

Section: Introductionmentioning

confidence: 99%

Glucose and glutamine metabolism in relation to mutational status in NSCLC histological subtypes

et al. 2019

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BackgroundBoth hypoxia and oncogenic mutations rewire tumor metabolism. In this study, glucose and glutamine metabolism‐related markers were examined in stage I ‐ resectable stage IIIA non‐small cell lung cancer (NSCLC). Furthermore, expression of metabolism‐related markers was correlated with mutational status to examine mutations associated with rewired tumor metabolism.MethodsMutation analysis was performed for 97 tumors. Glucose and glutamine metabolism‐related marker expression was measured by immunofluorescent staining (protein) and qPCR (mRNA) (n = 81).ResultsGlutamine metabolism‐related markers were significantly higher in adeno‐ than squamous cell NSCLCs. Glucose transporter 1 (GLUT1) protein expression was higher in solid compared to lepidic adenocarcinomas (P < 0.01). In adenocarcinomas, mRNA expression of glutamine transporter SLC1A5 correlated with tumor size (r(p) = 0.41, P = 0.005). Furthermore, SLC1A5 protein expression was significantly higher in adenocarcinomas with worse pTNM stage (r(s) = 0.39, P = 0.009). EGFR‐mutated tumors showed lower GLUT1 protein (P = 0.017), higher glutaminase 2 (GLS2) protein (P = 0.025) and higher GLS2 mRNA expression (P = 0.004), compared to EGFR wild‐type tumors. GLS mRNA expression was higher in KRAS‐mutated tumors (P = 0.019). TP53‐mutated tumors showed higher GLUT1 expression (P = 0.009).ConclusionsNSCLC is a heterogeneous disease, with differences in mutational status and metabolism‐related marker expression between adeno‐ and squamous cell NSCLCs, and also within adenocarcinoma subtypes. GLUT1 and SLC1A5 expression correlate with aggressive tumor behavior in adenocarcinomas but not in squamous cell NSCLCs. Therefore, these markers could steer treatment modification for subgroups of adenocarcinoma patients. TP53, EGFR and KRAS mutations are associated with expression of glucose and glutamine metabolism‐related markers in NSCLC.

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“…Mechanisms of this resistance include the development of a second-site EGFR resistance mutation ( T790M ); the activation of parallel signaling pathways, including cMET, HER2, FGFR, Mer and AXL; up regulation of SCRN1; epithelial–mesenchymal transition (EMT); and small cell transformation [4–11]. Drugs that inhibit glutaminase C, JAK, Mer and Src are effective in some EGFR TKI resistance models [8–10, 12]. In addition, resistance to EGFR inhibition can result from an innate mechanism whereby the short-term inhibition of downstream AKT leads to decreased Ets1 expression and subsequently decreased levels of DUSP6, the negative regulator of ERK1/2 [13].…”

Section: Introductionmentioning

confidence: 99%

Polo-like kinase 1 inhibition diminishes acquired resistance to epidermal growth factor receptor inhibition in non-small cell lung cancer with T790M mutations

et al. 2016

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Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are effective against non-small cell lung cancer (NSCLC) with activating EGFR mutations, but resistance is inevitable. Mechanisms of acquired resistance include T790M mutations and epithelial–mesenchymal transition (EMT). One potential strategy for overcoming this resistance is the inhibition of polo-like kinase 1 (PLK1) based on our previous studies showing that mesenchymal NSCLC cell lines are more sensitive to PLK1 inhibition than epithelial cell lines. To determine the extent to which PLK1 inhibition overcomes EGFR TKI resistance we measured the effects of the PLK1 inhibitor volasertib alone and in combination with the EGFR inhibitor erlotinib in vitro and in vivo in EGFR mutant NSCLC cell lines with acquired resistance to erlotinib. Two erlotinib-resistant cell lines that underwent EMT had higher sensitivity to volasertib, which caused G2/M arrest and apoptosis, than their parental cells. In all NSCLC cell lines with T790M mutations, volasertib markedly reduced erlotinib resistance. All erlotinib-resistant NSCLC cell lines with T790M mutations had higher sensitivity to erlotinib plus volasertib than to erlotinib alone, and the combination treatment caused G2/M arrest and apoptosis. Compared with either agent alone, the combination treatment also caused significantly more DNA damage and greater reductions in tumor size. Our results suggest that PLK1 inhibition is clinically effective against NSCLC that becomes resistant to EGFR inhibition through EMT or the acquisition of a T790M mutation. These results uncover new functions of PLK1 inhibition in the treatment of NSCLC with acquired resistance to EGFR TKIs.

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Inhibition of mitochondrial glutaminase activity reverses acquired erlotinib resistance in non-small cell lung cancer

Cited by 39 publications

References 45 publications

Erratum: From Krebs to clinic: glutamine metabolism to cancer therapy

Erratum: From Krebs to clinic: glutamine metabolism to cancer therapy

Glucose and glutamine metabolism in relation to mutational status in NSCLC histological subtypes

Polo-like kinase 1 inhibition diminishes acquired resistance to epidermal growth factor receptor inhibition in non-small cell lung cancer with T790M mutations

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