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

Introduction: [C]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 [C]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), HCC827 (erlotinib-resistant, delE746-A750 and T790M) and HCC827 (erlotinib-resistant, delE746-A750 and MET amplification). BALB/c nude mice with subcutaneous tumor xenografts underwent two consecutive [C]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 (V) of [C]erlotinib in tumors.

Results: In vitro experiments revealed significantly higher uptake of [C]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 [C]erlotinib uptake (-19% to -66%). In both PET scans and for all four studied cell lines there were no significant differences in tumoral [C]erlotinib V values. For all three NSCLC cell lines, but not for the A-431 cell line, tumoral V 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 [C]erlotinib between erlotinib-sensitive and erlotinib-resistant NSCLC cells. Our findings suggest that [C]erlotinib PET will not be suitable to distinguish erlotinib-sensitive NSCLC tumors from tumors with acquired resistance to erlotinib.