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 ¹⁸F-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 ${\text{R}}_2{}^{\ast }$ , lower hyperoxia-induced $\Delta {\text{R}}_2{}^{\ast }$ 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 ΔR₁ or water diffusivity between the CAL^R and CAL^S xenografts. PET revealed significantly higher relative uptake of ¹⁸F-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.