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A comparative PET imaging study with the reversible and irreversible EGFR tyrosine kinase inhibitors [(11)C]erlotinib and [(18)F]afatinib in lung cancer-bearing mice.

Slobbe P, Windhorst AD, Stigter-van Walsum M, Smit EF, Niessen HG, Solca F, Stehle G, van Dongen GA, Poot AJ - EJNMMI Res (2015)

Bottom Line: Additionally, the effect of drug efflux transporter permeability glycoprotein (P-gp) on the tumor uptake of tracers was explored by therapeutic blocking with tariquidar.Under P-gp blocking conditions, no significant changes in tumor-to-background ratio were observed; however, [(18)F]afatinib demonstrated better tumor retention in all xenograft models.TKI-PET provides a method to image sensitizing mutations and can be a valuable tool to compare the distinguished targeting properties of TKIs in vivo.

View Article: PubMed Central - PubMed

Affiliation: Department of Radiology and Nuclear Medicine, VU University Medical Center, De Boelelaan 1117, Amsterdam, 1081 HV The Netherlands ; Department of Otolaryngology/Head and Neck Surgery, VU University Medical Center, De Boelelaan 1117, Amsterdam, 1081 HV The Netherlands.

ABSTRACT

Background: Tyrosine kinase inhibitors (TKIs) have experienced a tremendous boost in the last decade, where more than 15 small molecule TKIs have been approved by the FDA. Unfortunately, despite their promising clinical successes, a large portion of patients remain unresponsive to these targeted drugs. For non-small cell lung cancer (NSCLC), the effectiveness of TKIs is dependent on the mutational status of epidermal growth factor receptor (EGFR). The exon 19 deletion as well as the L858R point mutation lead to excellent sensitivity to TKIs such as erlotinib and gefitinib; however, despite initial good response, most patients invariably develop resistance against these first-generation reversible TKIs, e.g., via T790M point mutation. Second-generation TKIs that irreversibly bind to EGFR wild-type and mutant isoforms have therefore been developed and one of these candidates, afatinib, has now reached the market. Whether irreversible TKIs differ from reversible TKIs in their in vivo tumor-targeting properties is, however, not known and is the subject of the present study.

Methods: Erlotinib was labeled with carbon-11 and afatinib with fluorine-18 without modifying the structure of these compounds. A preclinical positron emission tomography (PET) study was performed in mice bearing NSCLC xenografts with a representative panel of mutations: an EGFR-WT xenograft cell line (A549), an acquired treatment-resistant L858R/T790M mutant (H1975), and a treatment-sensitive exon 19 deleted mutant (HCC827). PET imaging was performed in these xenografts with both tracers. Additionally, the effect of drug efflux transporter permeability glycoprotein (P-gp) on the tumor uptake of tracers was explored by therapeutic blocking with tariquidar.

Results: Both tracers only demonstrated selective tumor uptake in the HCC827 xenograft line (tumor-to-background ratio, [(11)C]erlotinib 1.9 ± 0.5 and [(18)F]afatinib 2.3 ± 0.4), thereby showing the ability to distinguish sensitizing mutations in vivo. No major differences were observed in the kinetics of the reversible and the irreversible tracers in each of the xenograft models. Under P-gp blocking conditions, no significant changes in tumor-to-background ratio were observed; however, [(18)F]afatinib demonstrated better tumor retention in all xenograft models.

Conclusions: TKI-PET provides a method to image sensitizing mutations and can be a valuable tool to compare the distinguished targeting properties of TKIs in vivo.

No MeSH data available.


Related in: MedlinePlus

Chemical structures of erlotinib and afatinib.
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Fig1: Chemical structures of erlotinib and afatinib.

Mentions: Erlotinib (Tarceva®, Roche, Basel, Switzerland; 1, Figure 1) is a first-generation reversible 4-anilinoquinazoline inhibitor of EGFR and was approved in 2004 for NSCLC treatment of patients with locally advanced or metastatic NSCLC in combination with chemotherapy. No patient selection based on mutation analysis was performed at the time of approval and all eligible NSCLC patients were treated with erlotinib [14]. In the following years, it became clear that EGFR mutations are of great importance for the efficacy of erlotinib (and other first-generation EGFR TKIs, such as gefitinib), and erlotinib was subsequently approved in 2013 as a first-line treatment for patients whose tumors harbor an exon 19 deletion or an exon 20 point mutation [15]. TKI-PET imaging with the tracer [11C]erlotinib was first reported by Memon et al. in a seminal study demonstrating selective uptake in treatment-sensitive xenografts with mutation-activated EGFR. In this pre-clinical study, no metabolite analysis was performed [16]. Subsequently, a clinical evaluation was performed by the same group in NSCLC patients demonstrating uptake in a subgroup of patients; however, in that study, mutational status was not reported [17]. The first proof-of-principle in a clinical study was recently published by Bahce et al. in which NCSLC patients with responsive EGFR exon 19 deleted tumors showed increased uptake of [11C]erlotinib when compared to patients with non-responsive EGFR wild-type tumors. Furthermore, in these patients, a metabolite analysis was performed demonstrating circa 50% intact [11C]erlotinib in plasma and mainly polar metabolites. This was the first study ever demonstrating the predictive potential of an EGFR TKI-PET tracer; therefore, this tracer was used as ‘gold standard’ reference in this study [18].Figure 1


A comparative PET imaging study with the reversible and irreversible EGFR tyrosine kinase inhibitors [(11)C]erlotinib and [(18)F]afatinib in lung cancer-bearing mice.

Slobbe P, Windhorst AD, Stigter-van Walsum M, Smit EF, Niessen HG, Solca F, Stehle G, van Dongen GA, Poot AJ - EJNMMI Res (2015)

Chemical structures of erlotinib and afatinib.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4385286&req=5

Fig1: Chemical structures of erlotinib and afatinib.
Mentions: Erlotinib (Tarceva®, Roche, Basel, Switzerland; 1, Figure 1) is a first-generation reversible 4-anilinoquinazoline inhibitor of EGFR and was approved in 2004 for NSCLC treatment of patients with locally advanced or metastatic NSCLC in combination with chemotherapy. No patient selection based on mutation analysis was performed at the time of approval and all eligible NSCLC patients were treated with erlotinib [14]. In the following years, it became clear that EGFR mutations are of great importance for the efficacy of erlotinib (and other first-generation EGFR TKIs, such as gefitinib), and erlotinib was subsequently approved in 2013 as a first-line treatment for patients whose tumors harbor an exon 19 deletion or an exon 20 point mutation [15]. TKI-PET imaging with the tracer [11C]erlotinib was first reported by Memon et al. in a seminal study demonstrating selective uptake in treatment-sensitive xenografts with mutation-activated EGFR. In this pre-clinical study, no metabolite analysis was performed [16]. Subsequently, a clinical evaluation was performed by the same group in NSCLC patients demonstrating uptake in a subgroup of patients; however, in that study, mutational status was not reported [17]. The first proof-of-principle in a clinical study was recently published by Bahce et al. in which NCSLC patients with responsive EGFR exon 19 deleted tumors showed increased uptake of [11C]erlotinib when compared to patients with non-responsive EGFR wild-type tumors. Furthermore, in these patients, a metabolite analysis was performed demonstrating circa 50% intact [11C]erlotinib in plasma and mainly polar metabolites. This was the first study ever demonstrating the predictive potential of an EGFR TKI-PET tracer; therefore, this tracer was used as ‘gold standard’ reference in this study [18].Figure 1

Bottom Line: Additionally, the effect of drug efflux transporter permeability glycoprotein (P-gp) on the tumor uptake of tracers was explored by therapeutic blocking with tariquidar.Under P-gp blocking conditions, no significant changes in tumor-to-background ratio were observed; however, [(18)F]afatinib demonstrated better tumor retention in all xenograft models.TKI-PET provides a method to image sensitizing mutations and can be a valuable tool to compare the distinguished targeting properties of TKIs in vivo.

View Article: PubMed Central - PubMed

Affiliation: Department of Radiology and Nuclear Medicine, VU University Medical Center, De Boelelaan 1117, Amsterdam, 1081 HV The Netherlands ; Department of Otolaryngology/Head and Neck Surgery, VU University Medical Center, De Boelelaan 1117, Amsterdam, 1081 HV The Netherlands.

ABSTRACT

Background: Tyrosine kinase inhibitors (TKIs) have experienced a tremendous boost in the last decade, where more than 15 small molecule TKIs have been approved by the FDA. Unfortunately, despite their promising clinical successes, a large portion of patients remain unresponsive to these targeted drugs. For non-small cell lung cancer (NSCLC), the effectiveness of TKIs is dependent on the mutational status of epidermal growth factor receptor (EGFR). The exon 19 deletion as well as the L858R point mutation lead to excellent sensitivity to TKIs such as erlotinib and gefitinib; however, despite initial good response, most patients invariably develop resistance against these first-generation reversible TKIs, e.g., via T790M point mutation. Second-generation TKIs that irreversibly bind to EGFR wild-type and mutant isoforms have therefore been developed and one of these candidates, afatinib, has now reached the market. Whether irreversible TKIs differ from reversible TKIs in their in vivo tumor-targeting properties is, however, not known and is the subject of the present study.

Methods: Erlotinib was labeled with carbon-11 and afatinib with fluorine-18 without modifying the structure of these compounds. A preclinical positron emission tomography (PET) study was performed in mice bearing NSCLC xenografts with a representative panel of mutations: an EGFR-WT xenograft cell line (A549), an acquired treatment-resistant L858R/T790M mutant (H1975), and a treatment-sensitive exon 19 deleted mutant (HCC827). PET imaging was performed in these xenografts with both tracers. Additionally, the effect of drug efflux transporter permeability glycoprotein (P-gp) on the tumor uptake of tracers was explored by therapeutic blocking with tariquidar.

Results: Both tracers only demonstrated selective tumor uptake in the HCC827 xenograft line (tumor-to-background ratio, [(11)C]erlotinib 1.9 ± 0.5 and [(18)F]afatinib 2.3 ± 0.4), thereby showing the ability to distinguish sensitizing mutations in vivo. No major differences were observed in the kinetics of the reversible and the irreversible tracers in each of the xenograft models. Under P-gp blocking conditions, no significant changes in tumor-to-background ratio were observed; however, [(18)F]afatinib demonstrated better tumor retention in all xenograft models.

Conclusions: TKI-PET provides a method to image sensitizing mutations and can be a valuable tool to compare the distinguished targeting properties of TKIs in vivo.

No MeSH data available.


Related in: MedlinePlus