Evaluating Imaging Biomarkers of Acquired Resistance to Targeted EGFR Therapy in Xenograft Models of Human Head and Neck Squamous Cell Carcinoma.

Lauren C J Baker,Terry J Spinks,Jessica K R Boult,Elise Y Lepicard,Gary Box,Gabriela Kramer-Marek,Arti Sikka,Suzanne A Eccles,Simon P Robinson,Yann Jamin,Martin O Leach,Carol Box,Jonathan M Price

doi:10.3389/fonc.2018.00271

Abstract

Background: Overexpression of EGFR is a negative prognostic factor in head and neck squamous cell carcinoma (HNSCC). Patients with HNSCC who respond to EGFR-targeted tyrosine kinase inhibitors (TKIs) eventually develop acquired resistance. Strategies to identify HNSCC patients likely to benefit from EGFR-targeted therapies, together with biomarkers of treatment response, would have clinical value.Methods: Functional MRI and 18F-FDG PET were used to visualize and quantify imaging biomarkers associated with drug response within size-matched EGFR TKI-resistant CAL 27 (CALR) and sensitive (CALS) HNSCC xenografts in vivo, and pathological correlates sought.Results: Intrinsic susceptibility, oxygen-enhanced and dynamic contrast-enhanced MRI revealed significantly slower baseline , lower hyperoxia-induced and volume transfer constant Ktrans in the CALR tumors which were associated with significantly lower Hoechst 33342 uptake and greater pimonidazole-adduct formation. There was no difference in oxygen-induced ΔR1 or water diffusivity between the CALR and CALS xenografts. PET revealed significantly higher relative uptake of 18F-FDG in the CALR cohort, which was associated with significantly greater Glut-1 expression.Conclusions: CALR xenografts established from HNSCC cells resistant to EGFR TKIs are more hypoxic, poorly perfused and glycolytic than sensitive CALS tumors. MRI combined with PET can be used to non-invasively assess HNSCC response/resistance to EGFR inhibition.

Highlights

Head and neck squamous cell carcinoma (HNSCC) is a significant cause of morbidity and mortality, with almost 700,000 new cases estimated annually, worldwide [1]
HNSCC xenografts derived from epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs)-resistant CALR cells grew more rapidly than CALS tumors, as previously reported
The initial response and subsequent relapse of HNSCC patients treated with EGFR TKIs is well documented [13, 14]

Summary

Introduction

Head and neck squamous cell carcinoma (HNSCC) is a significant cause of morbidity and mortality, with almost 700,000 new cases estimated annually, worldwide [1]. Clinical responses to first generation EGFR tyrosine kinase inhibitors (TKIs), such as gefitinib or erlotinib, in HNSCC were disappointing [11]. The overwhelming majority of patients who initially respond to targeted therapies only achieve stable disease of short duration and acquired resistance usually manifests within 6–12 months [13,14,15]. Overexpression of EGFR is a negative prognostic factor in head and neck squamous cell carcinoma (HNSCC). Patients with HNSCC who respond to EGFR-targeted tyrosine kinase inhibitors (TKIs) eventually develop acquired resistance. Strategies to identify HNSCC patients likely to benefit from EGFR-targeted therapies, together with biomarkers of treatment response, would have clinical value. Methods: Functional MRI and 18F-FDG PET were used to visualize and quantify imaging biomarkers associated with drug response within size-matched EGFR TKI-resistant CAL 27 (CALR) and sensitive (CALS) HNSCC xenografts in vivo, and pathological correlates sought

Objectives

Methods

Results

Conclusion