Frontiers in Oncology (Jul 2018)
Evaluating Imaging Biomarkers of Acquired Resistance to Targeted EGFR Therapy in Xenograft Models of Human Head and Neck Squamous Cell Carcinoma
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 R2∗, lower hyperoxia-induced ΔR2∗ 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.
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