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

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 ¹⁸ F-FDG PET were used to visualize and quantify imaging biomarkers associated with drug response within size-matched EGFR TKI-resistant CAL 27 (CAL ^R ) and sensitive (CAL ^S ) HNSCC xenografts in vivo , and pathological correlates sought. Results: Intrinsic susceptibility, oxygen-enhanced and dynamic contrast-enhanced MRI revealed significantly slower baseline R 2 ∗ , lower hyperoxia-induced Δ R 2 ∗ and volume transfer constant K ^trans in the CAL ^R tumors which were associated with significantly lower Hoechst 33342 uptake and greater pimonidazole-adduct formation. There was no difference in oxygen-induced ΔR ₁ or water diffusivity between the CAL ^R and CAL ^S xenografts. PET revealed significantly higher relative uptake of ¹⁸ F-FDG in the CAL ^R cohort, which was associated with significantly greater Glut-1 expression. Conclusions: CAL ^R xenografts established from HNSCC cells resistant to EGFR TKIs are more hypoxic, poorly perfused and glycolytic than sensitive CAL ^S tumors. MRI combined with PET can be used to non-invasively assess HNSCC response/resistance to EGFR inhibition.