Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
EJNMMI Research
Published in: EJNMMI Research 1/2015

Open Access 01-12-2015 | Original research

Identifying erlotinib-sensitive non-small cell lung carcinoma tumors in mice using [11C]erlotinib PET

Authors: Galith Abourbeh, Batel Itamar, Olga Salnikov, Sergey Beltsov, Eyal Mishani

Published in: EJNMMI Research | Issue 1/2015

Login to get access

Abstract

Background

Non-small cell lung carcinoma (NSCLC) represents approximately 80% of lung cancer cases, and over 60% of these tumors express the epidermal growth factor receptor (EGFR). Activating mutations in the tyrosine kinase (TK) domain of the EGFR are detected in 10% to 30% of NSCLC patients, and evidence of their presence is a prerequisite for initiation of first-line therapy with selective TK inhibitors (TKIs), such as gefitinib and erlotinib. To date, the selection of candidate patients for first-line treatment with EGFR TKIs requires an invasive tumor biopsy to affirm the mutational status of the receptor. This study was designed to evaluate whether positron emission tomography (PET) of NSCLC tumor-bearing mice using [11C]erlotinib could distinguish erlotinib-sensitive from erlotinib-insensitive or erlotinib-resistant tumors.

Methods

Four human NSCLC cell lines were employed, expressing either of the following forms of the EGFR: (i) the wild-type receptor (QG56 cells), (ii) a mutant with an exon 19 in-frame deletion (HCC827 cells), (iii) a mutant with the exon 21 L858R point mutation (NCI-H3255 cells), and (iv) a double mutant harboring the L858R and T790M mutations (NCI-H1975 cells). Sensitivity of each cell line to the anti-proliferative effect of erlotinib was determined in vitro. In vivo PET imaging studies following i.v. injection of [11C]erlotinib were carried out in nude mice bearing subcutaneous (s.c.) xenografts of the four cell lines.

Results

Cells harboring activating mutations in the EGFR TK domain (HCC827 and NCI-H3255) were approximately 1,000- and 100-fold more sensitive to erlotinib treatment in vitro, respectively, compared to the other two cell lines. [11C]Erlotinib PET scans could differentiate erlotinib-sensitive tumors from insensitive (QG56) or resistant (NCI-H1975) tumors already at 12 min after injection. Nonetheless, the uptake in HCC827 tumors was significantly higher than that in NCI-H3255, possibly reflecting differences in ATP and erlotinib affinities between the EGFR mutants.

Conclusions

[11C]Erlotinib imaging in mice differentiates erlotinib-sensitive NSCLC tumors from erlotinib-insensitive or erlotinib-resistant ones.
Literature
1.
Carnio S, Novello S, Mele T, Levra MG, Scagliotti GV. Extending survival of stage IV non-small cell lung cancer. Semin Oncol. 2014;41:69–92.CrossRefPubMed
2.
3.
Abourbeh G, Shir A, Mishani E, Ogris M, Rodl W, Wagner E, et al. PolyIC GE11 polyplex inhibits EGFR-overexpressing tumors. IUBMB Life. 2012;64:324–30.CrossRefPubMedCentralPubMed
4.
Chen P, Cameron R, Wang J, Vallis KA, Reilly RM. Antitumor effects and normal tissue toxicity of 111In-labeled epidermal growth factor administered to athymic mice bearing epidermal growth factor receptor-positive human breast cancer xenografts. J Nucl Med. 2003;44:1469–78.PubMed
5.
Mamot C, Drummond DC, Greiser U, Hong K, Kirpotin DB, Marks JD, et al. Epidermal growth factor receptor (EGFR)-targeted immunoliposomes mediate specific and efficient drug delivery to EGFR- and EGFRvIII-overexpressing tumor cells. Cancer Res. 2003;63:3154–61.PubMed
6.
Ratti M, Tomasello G. Emerging combination therapies to overcome resistance in EGFR-driven tumors. Anticancer Drugs. 2014;25:127–39.CrossRefPubMed
7.
Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med. 2004;350:2129–39.CrossRefPubMed
8.
Paez JG, Janne PA, Lee JC, Tracy S, Greulich H, Gabriel S, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science. 2004;304:1497–500.CrossRefPubMed
9.
Sordella R, Bell DW, Haber DA, Settleman J. Gefitinib-sensitizing EGFR mutations in lung cancer activate anti-apoptotic pathways. Science. 2004;305:1163–7.CrossRefPubMed
10.
Dillon B, Naidoo B, Knight H, Clark P. NICE guidance on erlotinib for first-line treatment of EGFR-TK mutation-positive advanced or metastatic non-small-cell lung cancer. Lancet Oncol. 2012;13:764–5.CrossRefPubMed
11.
Rosell R, Carcereny E, Gervais R, Vergnenegre A, Massuti B, Felip E, et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2012;13:239–46.CrossRefPubMed
12.
Riely GJ, Kris MG, Zhao B, Akhurst T, Milton DT, Moore E, et al. Prospective assessment of discontinuation and reinitiation of erlotinib or gefitinib in patients with acquired resistance to erlotinib or gefitinib followed by the addition of everolimus. Clin Cancer Res. 2007;13:5150–5.CrossRefPubMed
13.
Yu HA, Arcila ME, Rekhtman N, Sima CS, Zakowski MF, Pao W, et al. Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers. Clin Cancer Res. 2013;19:2240–7.CrossRefPubMedCentralPubMed
14.
Zhao J, Wang X, Xue L, Xu N, Ye X, Zeng H, et al. The use of mutation-specific antibodies in predicting the effect of EGFR-TKIs in patients with non-small-cell lung cancer. J Cancer Res Clin Oncol. 2014;140:849–57.CrossRefPubMed
15.
Peled N, Barash O, Tisch U, Ionescu R, Broza YY, Ilouze M, et al. Volatile fingerprints of cancer specific genetic mutations. Nanomedicine. 2013;9:758–66.CrossRefPubMedCentralPubMed
16.
Yeh HH, Ogawa K, Balatoni J, Mukhapadhyay U, Pal A, Gonzalez-Lepera C, et al. Molecular imaging of active mutant L858R EGF receptor (EGFR) kinase-expressing nonsmall cell lung carcinomas using PET/CT. Proc Natl Acad Sci U S A. 2011;108:1603–8.CrossRefPubMedCentralPubMed
17.
Abourbeh G, Dissoki S, Jacobson O, Litchi A, Ben Daniel R, Laki D, et al. Evaluation of radiolabeled ML04, a putative irreversible inhibitor of epidermal growth factor receptor, as a bioprobe for PET imaging of EGFR-overexpressing tumors. Nucl Med Biol. 2007;34:55–70.CrossRefPubMed
18.
Bahce I, Smit EF, Lubberink M, van der Veldt AA, Yaqub M, Windhorst AD, et al. Development of [(11)C]erlotinib positron emission tomography for in vivo evaluation of EGF receptor mutational status. Clin Cancer Res. 2012;19:183–93.CrossRefPubMed
19.
Memon AA, Jakobsen S, Dagnaes-Hansen F, Sorensen BS, Keiding S, Nexo E. Positron emission tomography (PET) imaging with [11C]-labeled erlotinib: a micro-PET study on mice with lung tumor xenografts. Cancer Res. 2009;69:873–8.CrossRefPubMed
20.
Memon AA, Weber B, Winterdahl M, Jakobsen S, Meldgaard P, Madsen HH, et al. PET imaging of patients with non-small cell lung cancer employing an EGF receptor targeting drug as tracer. Br J Cancer. 2011;105:1850–5.CrossRefPubMedCentralPubMed
21.
Meng X, Loo Jr BW, Ma L, Murphy JD, Sun X, Yu J. Molecular imaging with 11C-PD153035 PET/CT predicts survival in non-small cell lung cancer treated with EGFR-TKI: a pilot study. J Nucl Med. 2011;52:1573–9.CrossRefPubMed
22.
Mishani E, Hagooly A. Strategies for molecular imaging of epidermal growth factor receptor tyrosine kinase in cancer. J Nucl Med. 2009;50:1199–202.CrossRefPubMed
23.
Pal A, Glekas A, Doubrovin M, Balatoni J, Namavari M, Beresten T, et al. Molecular imaging of EGFR kinase activity in tumors with 124I-labeled small molecular tracer and positron emission tomography. Mol Imaging Biol. 2006;8:262–77.CrossRefPubMed
24.
Petrulli JR, Sullivan JM, Zheng MQ, Bennett DC, Charest J, Huang Y, et al. Quantitative analysis of [11C]-erlotinib PET demonstrates specific binding for activating mutations of the EGFR kinase domain. Neoplasia. 2013;15:1347–53.PubMedCentralPubMed
25.
Slobbe P, Poot AJ, Windhorst AD, van Dongen GA. PET imaging with small-molecule tyrosine kinase inhibitors: TKI-PET. Drug Discov Today. 2012;17:1175–87.CrossRefPubMed
26.
Su H, Seimbille Y, Ferl GZ, Bodenstein C, Fueger B, Kim KJ, et al. Evaluation of [(18)F]gefitinib as a molecular imaging probe for the assessment of the epidermal growth factor receptor status in malignant tumors. Eur J Nucl Med Mol Imaging. 2008;35:1089–99.CrossRefPubMed
27.
van Dongen GA, Poot AJ, Vugts DJ. PET imaging with radiolabeled antibodies and tyrosine kinase inhibitors: immuno-PET and TKI-PET. Tumour Biol. 2012;33:607–15.CrossRefPubMedCentralPubMed
28.
Weber B, Winterdahl M, Memon A, Sorensen BS, Keiding S, Sorensen L, et al. Erlotinib accumulation in brain metastases from non-small cell lung cancer: visualization by positron emission tomography in a patient harboring a mutation in the epidermal growth factor receptor. J Thorac Oncol. 2011;6:1287–9.CrossRefPubMed
29.
Zhang MR, Kumata K, Hatori A, Takai N, Toyohara J, Yamasaki T, et al. [11C]Gefitinib ([11c]Iressa): radiosynthesis, in vitro uptake, and in vivo imaging of intact murine fibrosarcoma. Mol Imaging Biol. 2010;12:181–91.CrossRefPubMed
30.
Dent MF, Hubbold L, Radford H, Wilson AP. The methylene blue colorimetric microassay for determining cell line response to growth factors. Cytotechnology. 1995;17:27–33.CrossRefPubMed
31.
Abourbeh G, Theze B, Maroy R, Dubois A, Brulon V, Fontyn Y, et al. Imaging microglial/macrophage activation in spinal cords of experimental autoimmune encephalomyelitis rats by positron emission tomography using the mitochondrial 18 kDa translocator protein radioligand [(1)(8)F]DPA-714. J Neurosci. 2012;32:5728–36.CrossRefPubMed
32.
Han SW, Kim TY, Hwang PG, Jeong S, Kim J, Choi IS, et al. Predictive and prognostic impact of epidermal growth factor receptor mutation in non-small-cell lung cancer patients treated with gefitinib. J Clin Oncol. 2005;23:2493–501.CrossRefPubMed
33.
Parra HS, Cavina R, Latteri F, Zucali PA, Campagnoli E, Morenghi E, et al. Analysis of epidermal growth factor receptor expression as a predictive factor for response to gefitinib (‘Iressa’, ZD1839) in non-small-cell lung cancer. Br J Cancer. 2004;91:208–12.PubMedCentralPubMed
34.
Conti PS, White C, Pieslor P, Molina A, Aussie J, Foster P. The role of imaging with (111)In-ibritumomab tiuxetan in the ibritumomab tiuxetan (Zevalin) regimen: results from a Zevalin Imaging Registry. J Nucl Med. 2005;46:1812–8.PubMed
35.
Druker BJ, Guilhot F, O'Brien SG, Gathmann I, Kantarjian H, Gattermann N, et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med. 2006;355:2408–17.CrossRefPubMed
36.
Teunissen JJ, Kwekkeboom DJ, Valkema R, Krenning EP. Nuclear medicine techniques for the imaging and treatment of neuroendocrine tumours. Endocr Relat Cancer. 2011;18 Suppl 1:S27–51.CrossRefPubMed
37.
Velikyan I, Sundin A, Sorensen J, Lubberink M, Sandstrom M, Garske-Roman U, et al. Quantitative and qualitative intrapatient comparison of 68Ga-DOTATOC and 68Ga-DOTATATE: net uptake rate for accurate quantification. J Nucl Med. 2014;55:204–10.CrossRefPubMed
38.
Cadranel J, Ruppert AM, Beau-Faller M, Wislez M. Therapeutic strategy for advanced EGFR mutant non-small-cell lung carcinoma. Crit Rev Oncol Hematol. 2013;88:477–93.CrossRefPubMed
39.
Sharma SV, Bell DW, Settleman J, Haber DA. Epidermal growth factor receptor mutations in lung cancer. Nat Rev Cancer. 2007;7:169–81.CrossRefPubMed
40.
Eckelman WC. The application of receptor theory to receptor-binding and enzyme-binding oncologic radiopharmaceuticals. Nucl Med Biol. 1994;21:759–69.CrossRefPubMed
41.
Carey KD, Garton AJ, Romero MS, Kahler J, Thomson S, Ross S, et al. Kinetic analysis of epidermal growth factor receptor somatic mutant proteins shows increased sensitivity to the epidermal growth factor receptor tyrosine kinase inhibitor, erlotinib. Cancer Res. 2006;66:8163–71.CrossRefPubMed
42.
Frings V, Yaqub M, Hoyng LL, Golla SS, Windhorst AD, Schuit RC, et al. Assessment of simplified methods to measure 18F-FLT uptake changes in EGFR-mutated non-small cell lung cancer patients undergoing EGFR tyrosine kinase inhibitor treatment. J Nucl Med. 2014;55:1417–23.CrossRefPubMed
43.
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
44.
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
45.
Sohn HJ, Yang YJ, Ryu JS, Oh SJ, Im KC, Moon DH, et al. [18F]Fluorothymidine positron emission tomography before and 7 days after gefitinib treatment predicts response in patients with advanced adenocarcinoma of the lung. Clin Cancer Res. 2008;14:7423–9.CrossRefPubMed
Metadata
Title
Identifying erlotinib-sensitive non-small cell lung carcinoma tumors in mice using [11C]erlotinib PET
Authors
Galith Abourbeh
Batel Itamar
Olga Salnikov
Sergey Beltsov
Eyal Mishani
Publication date
01-12-2015
Publisher
Springer Berlin Heidelberg
Published in
EJNMMI Research / Issue 1/2015
Electronic ISSN: 2191-219X
DOI
https://doi.org/10.1186/s13550-014-0080-0

Other articles of this Issue 1/2015

EJNMMI Research 1/2015 Go to the issue

Original research

99mTc-MDP bone scintigraphy of the hand: comparing the use of novel cadmium zinc telluride (CZT) and routine NaI(Tl) detectors

Original research

64Cu-DOTA-trastuzumab PET imaging and HER2 specificity of brain metastases in HER2-positive breast cancer patients

Original research

Optimisation of quantitative lung SPECT applied to mild COPD: a software phantom simulation study

Original research

Gene expression signature in mouse thyroid tissue after 131I and 211At exposure

Original research

Non-invasive imaging of implanted peritoneal carcinomatosis in mice using PET and bioluminescence imaging

Original research

Role of CD8-positive cells in radioimmunotherapy utilizing 177Lu-mAbs in an immunocompetent rat colon carcinoma model