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Identifying erlotinib-sensitive non-small cell lung carcinoma tumors in mice using [(11)C]erlotinib PET
Galith Abourbeh1, Batel Itamar1, Olga Salnikov1
1Cyclotron-Radiochemistry-MicroPET Unit, Hadassah Hebrew University Hospital, Jerusalem, 91120 Israel.
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 [(11)C]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 [(11)C]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. [(11)C]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:
[(11)C]Erlotinib imaging in mice differentiates erlotinib-sensitive NSCLC tumors from erlotinib-insensitive or erlotinib-resistant ones.
Insights
Positron emission tomography (PET) with [(11)C]erlotinib can non-invasively distinguish epidermal growth factor receptor (EGFR) mutated non-small cell lung carcinoma (NSCLC) tumors sensitive to erlotinib from resistant ones.
Area of Science:
- Oncology
- Radiochemistry
- Molecular Imaging
Background:
- Non-small cell lung carcinoma (NSCLC) accounts for most lung cancers, with EGFR mutations common in tumors.
- EGFR tyrosine kinase inhibitors (TKIs) like erlotinib are first-line treatments, but require invasive biopsy for mutation status confirmation.
- Non-invasive methods are needed to assess tumor sensitivity to EGFR TKIs.
Purpose of the Study:
- To evaluate [(11)C]erlotinib positron emission tomography (PET) for differentiating erlotinib-sensitive from insensitive or resistant NSCLC tumors in vivo.
- To assess the potential of PET imaging as a non-invasive tool for patient selection in EGFR-TKI therapy.
Main Methods:
- Four human NSCLC cell lines with varying EGFR forms (wild-type, exon 19 deletion mutant, L858R mutant, double mutant) were used.
- In vitro sensitivity to erlotinib was determined.
- In vivo PET imaging was performed in mice bearing subcutaneous xenografts after [(11)C]erlotinib injection.
Main Results:
- Activating EGFR mutations conferred significant in vitro sensitivity to erlotinib.
- [(11)C]Erlotinib PET successfully differentiated sensitive tumors from insensitive or resistant ones as early as 12 minutes post-injection.
- Tumor uptake varied between sensitive mutant cell lines, potentially due to differences in EGFR affinities.
Conclusions:
- [(11)C]Erlotinib PET imaging in mice can effectively distinguish erlotinib-sensitive NSCLC tumors from insensitive or resistant ones.
- This imaging approach may offer a non-invasive alternative to tumor biopsy for guiding EGFR-TKI treatment selection.
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