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

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

JOURNAL=Frontiers in Oncology

VOLUME=8

YEAR=2018

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2018.00271

DOI=10.3389/fonc.2018.00271

ISSN=2234-943X

ABSTRACT=<p><bold>Background:</bold> 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.</p><p><bold>Methods:</bold> Functional MRI and <sup>18</sup>F-FDG PET were used to visualize and quantify imaging biomarkers associated with drug response within size-matched EGFR TKI-resistant CAL 27 (CAL<sup>R</sup>) and sensitive (CAL<sup>S</sup>) HNSCC xenografts <italic>in vivo</italic>, and pathological correlates sought.</p><p><bold>Results:</bold> Intrinsic susceptibility, oxygen-enhanced and dynamic contrast-enhanced MRI revealed significantly slower baseline <inline-formula><mml:math id="M1" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:msub><mml:mtext>R</mml:mtext><mml:mn>2</mml:mn></mml:msub><mml:msup><mml:mrow></mml:mrow><mml:mo>∗</mml:mo></mml:msup></mml:mrow></mml:math></inline-formula>, lower hyperoxia-induced <inline-formula><mml:math id="M2" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:mo>Δ</mml:mo><mml:msub><mml:mtext>R</mml:mtext><mml:mn>2</mml:mn></mml:msub><mml:msup><mml:mrow></mml:mrow><mml:mo>∗</mml:mo></mml:msup></mml:mrow></mml:math></inline-formula> and volume transfer constant K<sup>trans</sup> in the CAL<sup>R</sup> tumors which were associated with significantly lower Hoechst 33342 uptake and greater pimonidazole-adduct formation. There was no difference in oxygen-induced ΔR<sub>1</sub> or water diffusivity between the CAL<sup>R</sup> and CAL<sup>S</sup> xenografts. PET revealed significantly higher relative uptake of <sup>18</sup>F-FDG in the CAL<sup>R</sup> cohort, which was associated with significantly greater Glut-1 expression.</p><p><bold>Conclusions:</bold> CAL<sup>R</sup> xenografts established from HNSCC cells resistant to EGFR TKIs are more hypoxic, poorly perfused and glycolytic than sensitive CAL<sup>S</sup> tumors. MRI combined with PET can be used to non-invasively assess HNSCC response/resistance to EGFR inhibition.</p>