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EJNMMI Research
Published in: EJNMMI Research 1/2016

Open Access 01-12-2016 | Original research

Early 18F-FDG uptake as a reliable imaging biomarker of T790M-mediated resistance but not MET amplification in non-small cell lung cancer treated with EGFR tyrosine kinase inhibitors

Authors: Viviana De Rosa, Francesca Iommelli, Marcello Monti, Ciro Gabriele Mainolfi, Rosa Fonti, Silvana Del Vecchio

Published in: EJNMMI Research | Issue 1/2016

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Abstract

Background

The two main mechanisms of resistance to EGFR tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC) are the occurrence of T790M secondary mutation in the kinase domain of EGFR and MET amplification. The aim of the present study was to test whether early changes of 18F-fluorodeoxyglucose (18F-FDG) uptake in animal models bearing erlotinib-resistant NSCLC may have different imaging patterns of response to erlotinib depending on the molecular mechanisms underlying resistance.
Animal tumor models were developed using NSCLC H1975 cells bearing the T790M mutation and H1993 cells with MET amplification. Nude mice bearing erlotinib-resistant H1975 and H1993 xenografts (four animals for each cell line and for each treatment) were subjected to 18F-FDG PET/CT scan before and immediately after treatment (50 mg/kg p.o. for 3 days) with erlotinib, WZ4002, crizotinib, or vehicle. A three-dimensional region of interest analysis was performed to determine the percent change of 18F-FDG uptake in response to treatment. At the end of the imaging studies, tumors were removed and analyzed for glycolytic and mitochondrial proteins as well as levels of cyclin D1.

Results

Imaging studies with 18F-FDG PET/CT in H1975 tumor-bearing mice showed a reduction of 18F-FDG uptake of 25.87 % ± 8.93 % after treatment with WZ4002 whereas an increase of 18F-FDG uptake up to 23.51 % ± 9.72 % was observed after treatment with erlotinib or vehicle. Conversely, H1993 tumors showed a reduction of 18F-FDG uptake after treatment with both crizotinib (14.70 % ± 1.30 %) and erlotinib (18.40 % ± 9.19 %) and an increase of tracer uptake in vehicle-treated (56.65 % ± 5.65 %) animals. The in vivo reduction of 18F-FDG uptake was always associated with downregulation of HKII and p-PKM2 Tyr105 glycolytic proteins and upregulation of mitochondrial complexes (subunits I–IV) in excised tumors.

Conclusions

18F-FDG uptake is a reliable imaging biomarker of T790M-mediated resistance and its reversal in NSCLC whereas it may not be accurate in the detection of MET-mediated resistance.
Literature
1.
2.
Sequist LV, Martins RG, Spigel D, Grunberg SM, Spira A, Janne PA, et al. First-line gefitinib in patients with advanced non-small-cell lung cancer harboring somatic EGFR mutations. J Clin Oncol. 2008;26:2442–9.CrossRefPubMed
3.
Lee CK, Wu YL, Ding PN, Lord SJ, Inoue A, Zhou C, et al. Impact of specific epidermal growth factor receptor (EGFR) mutations and clinical characteristics on outcomes after treatment with EGFR tyrosine kinase inhibitors versus chemotherapy in EGFR-mutant lung cancer: a meta-analysis. J Clin Oncol. 2015;33:1958–65.CrossRefPubMed
4.
Gazdar AF. Activating and resistance mutations of EGFR in non-small-cell lung cancer: role in clinical response to EGFR tyrosine kinase inhibitors. Oncogene. 2009;28 Suppl 1:S24–31.CrossRefPubMedPubMedCentral
5.
6.
Engelman JA, Janne PA. Mechanisms of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer. Clin Cancer Res. 2008;14:2895–9.CrossRefPubMed
7.
Costa DB, Nguyen KS, Cho BC, Sequist LV, Jackman DM, Riely GJ, et al. Effects of erlotinib in EGFR mutated non-small cell lung cancers with resistance to gefitinib. Clin Cancer Res. 2008;14:7060–7.CrossRefPubMedPubMedCentral
8.
Engelman JA, Zejnullahu K, Mitsudomi T, Song Y, Hyland C, Park JO, et al. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science. 2007;316:1039–43.CrossRefPubMed
9.
Hicks RJ. Role of 18F-FDG PET in assessment of response in non-small cell lung cancer. J Nucl Med. 2009;50 Suppl 1:31S–42S.CrossRefPubMed
10.
11.
Mileshkin L, Hicks RJ, Hughes BG, Mitchell PL, Charu V, Gitlitz BJ, et al. Changes in 18F-fluorodeoxyglucose and 18F-fluorodeoxythymidine positron emission tomography imaging in patients with non-small cell lung cancer treated with erlotinib. Clin Cancer Res. 2011;17:3304–15.CrossRefPubMed
12.
Zander T, Scheffler M, Nogova L, Kobe C, Engel-Riedel W, Hellmich M, et al. Early prediction of nonprogression in advanced non-small-cell lung cancer treated with erlotinib by using [(18)F] fluorodeoxyglucose and [(18)F] fluorothymidine positron emission tomography. J Clin Oncol. 2011;29:1701–8.CrossRefPubMed
13.
Takahashi R, Hirata H, Tachibana I, Shimosegawa E, Inoue A, Nagatomo I, et al. Early [18F] fluorodeoxyglucose positron emission tomography at two days of gefitinib treatment predicts clinical outcome in patients with adenocarcinoma of the lung. Clin Cancer Res. 2012;18:220–8.CrossRefPubMed
14.
Kobe C, Scheffler M, Holstein A, Zander T, Nogova L, Lammertsma AA, et al. Predictive value of early and late residual 18F-fluorodeoxyglucose and 18F-fluorothymidine uptake using different SUV measurements in patients with non-small-cell lung cancer treated with erlotinib. Eur J Nucl Med Mol Imaging. 2012;39:1117–27.CrossRefPubMed
15.
Su H, Bodenstein C, Dumont RA, Seimbille Y, Dubinett S, Phelps ME, et al. Monitoring tumor glucose utilization by positron emission tomography for the prediction of treatment response to epidermal growth factor receptor kinase inhibitors. Clin Cancer Res. 2006;12:5659–67.CrossRefPubMed
16.
De Rosa V, Iommelli F, Monti M, Fonti R, Votta G, Stoppelli MP, et al. Reversal of Warburg effect and reactivation of oxidative phosphorylation by differential inhibition of EGFR signaling pathways in Non-small cell lung cancer. Clin Cancer Res. 2015;21:5110–20.CrossRefPubMed
17.
Rosell R, Molina MA, Costa C, Simonetti S, Gimenez-Capitan A, Bertran-Alamillo J, et al. Pretreatment EGFR T790M mutation and BRCA1 mRNA expression in erlotinib-treated advanced non-small-cell lung cancer patients with EGFR mutations. Clin Cancer Res. 2011;17:1160–8.CrossRefPubMed
18.
Kubo T, Yamamoto H, Lockwood WW, Valencia I, Soh J, Peyton M, et al. MET gene amplification or EGFR mutation activate MET in lung cancers untreated with EGFR tyrosine kinase inhibitors. Int J Cancer. 2009;124:1778–84.CrossRefPubMedPubMedCentral
19.
Zhao X, Weir BA, LaFramboise T, Lin M, Beroukhim R, Garraway L, et al. Homozygous deletions and chromosome amplifications in human lung carcinomas revealed by single nucleotide polymorphism array analysis. Cancer Res. 2005;65:5561–70.CrossRefPubMed
20.
Zhou W, Ercan D, Chen L, Yun CH, Li D, Capelletti M, et al. Novel mutant-selective EGFR kinase inhibitors against EGFR T790M. Nature. 2009;462:1070–4.CrossRefPubMedPubMedCentral
21.
Zannetti A, Iommelli F, Speranza A, Salvatore M, Del Vecchio S. 3′-deoxy-3′-18F-fluorothymidine PET/CT to guide therapy with epidermal growth factor receptor antagonists and Bcl-xL inhibitors in non-small cell lung cancer. J Nucl Med. 2012;53:443–50.CrossRefPubMed
22.
23.
Iommelli F, De Rosa V, Gargiulo S, Panico M, Monti M, Greco A, et al. Monitoring reversal of MET-mediated resistance to EGFR tyrosine kinase inhibitors in non-small cell lung cancer using 3′-deoxy-3′-[18F]-fluorothymidine positron emission tomography. Clin Cancer Res. 2014;20:4806–15.CrossRefPubMed
24.
Fonti R, Larobina M, Del Vecchio S, De Luca S, Fabbricini R, Catalano L, et al. Metabolic tumor volume assessed by 18F-FDG PET/CT for the prediction of outcome in patients with multiple myeloma. J Nucl Med. 2012;53:1829–35.CrossRefPubMed
25.
Wong N, Ojo D, Yan J, Tang D. PKM2 contributes to cancer metabolism. Cancer Lett. 2015;356:184–91.CrossRefPubMed
26.
27.
Iqbal MA, Gupta V, Gopinath P, Mazurek S, Bamezai RN. Pyruvate kinase M2 and cancer: an updated assessment. FEBS Lett. 2014;588:2685–92.CrossRefPubMed
28.
Iommelli F, De Rosa V, Fonti R, Del Vecchio S. Molecular imaging for detection of sensitivity and resistance to EGFR tyrosine kinase inhibitors in non-small cell lung cancer. Clin Transl Imaging. 2014;2:43–53.CrossRef
Metadata
Title
Early 18F-FDG uptake as a reliable imaging biomarker of T790M-mediated resistance but not MET amplification in non-small cell lung cancer treated with EGFR tyrosine kinase inhibitors
Authors
Viviana De Rosa
Francesca Iommelli
Marcello Monti
Ciro Gabriele Mainolfi
Rosa Fonti
Silvana Del Vecchio
Publication date
01-12-2016
Publisher
Springer Berlin Heidelberg
Published in
EJNMMI Research / Issue 1/2016
Electronic ISSN: 2191-219X
DOI
https://doi.org/10.1186/s13550-016-0229-0

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