[11C]Erlotinib PET cannot detect acquired erlotinib resistance in NSCLC tumor xenografts in mice.

Abstract

INTRODUCTION:

[11C]Erlotinib PET has shown promise to distinguish non-small cell lung cancer (NSCLC) tumors harboring the activating epidermal growth factor receptor (EGFR) mutation delE746-A750 from tumors with wild-type EGFR. To assess the suitability of [11C]erlotinib PET to detect the emergence of acquired erlotinib resistance in initially erlotinib-responsive tumors, we performed in vitro binding and PET experiments in mice bearing tumor xenografts using a range of different cancer cells, which were erlotinib-sensitive or exhibited clinically relevant resistance mechanisms to erlotinib.

METHODS:

The following cell lines were used for in vitro binding and PET experiments: the epidermoid carcinoma cell line A-431 (erlotinib-sensitive, wild-type EGFR) and the three NSCLC cell lines HCC827 (erlotinib-sensitive, delE746-A750), HCC827EPR (erlotinib-resistant, delE746-A750 and T790M) and HCC827ERLO (erlotinib-resistant, delE746-A750 and MET amplification). BALB/c nude mice with subcutaneous tumor xenografts underwent two consecutive [11C]erlotinib PET scans, a baseline scan and a second scan in which unlabeled erlotinib (10mg/kg) was co-injected. Logan graphical analysis was used to estimate total distribution volume (VT) of [11C]erlotinib in tumors.

RESULTS:

In vitro experiments revealed significantly higher uptake of [11C]erlotinib (5.2-fold) in the three NSCLC cell lines as compared to A-431 cells. In all four cell lines co-incubation with unlabeled erlotinib (1μM) led to significant reductions in [11C]erlotinib uptake (-19% to -66%). In both PET scans and for all four studied cell lines there were no significant differences in tumoral [11C]erlotinib VT values. For all three NSCLC cell lines, but not for the A-431 cell line, tumoral VT was significantly reduced following co-injection of unlabeled erlotinib (-20% to -35%).

CONCLUSIONS:

We found no significant differences in the in vitro and in vivo binding of [11C]erlotinib between erlotinib-sensitive and erlotinib-resistant NSCLC cells. Our findings suggest that [11C]erlotinib PET will not be suitable to distinguish erlotinib-sensitive NSCLC tumors from tumors with acquired resistance to erlotinib.

• Authors: Alexander Traxl, Taraneh Beikbaghban, Thomas Wanek, Kushtrim Kryeziu, Christine Pirker, Severin Mairinger, Johann Stanek, Thomas Filip, Michael Sauberer, Claudia Kuntner, Walter Berger, Oliver Langer
• Journal: Nuclear medicine and biology (Nucl Med Biol) Vol. 52 Pg. 7-15 (Sep 2017) ISSN: 1872-9614 [Electronic] United States
• PMID: 28575795 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 Elsevier Inc. All rights reserved.

Chemical References

• Erlotinib Hydrochloride
• EGFR protein, human
• ErbB Receptors

Topics

• Animals
• Carcinoma, Non-Small-Cell Lung (diagnostic imaging, drug therapy, metabolism, pathology)
• Cell Line, Tumor
• Cell Transformation, Neoplastic
• Drug Resistance, Neoplasm
• ErbB Receptors (metabolism)
• Erlotinib Hydrochloride (metabolism)
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Lung Neoplasms (diagnostic imaging, drug therapy, metabolism, pathology)
• Mice
• Positron-Emission Tomography