Investigation of MACROD2 as a Biomarker of Treatment Resistance in Human Papillomavirus-Related Head and Neck Cancer
Abstract
Head and neck squamous cell carcinoma (HNSCC) is the 6th most common cancer worldwide. Infection by human papillomavirus (HPV) has caused a rise in HNSCC cases. Unfortunately, a cohort of HPV+ HNSCC patients exhibit treatment resistance. At present, no known treatment resistant biomarkers have been identified. We completed genomic characterization of a local HPV+ HNSCC cohort and observed MACROD2 deletions in the treatment failure dataset. Functional validation revealed siRNA and shRNA MACROD2 knockdown in HNSCC cells led to elevated cell viability and colony formation. Interestingly, shMACROD2 caused no change in cisplatin sensitivity, but a significant increase in radiation resistance in HPV+ HNSCC. Transcriptomic, proteomic, and immunofluorescence studies demonstrated that MACROD2 depleted HPV+ HNSCC cells displayed elevated hypoxia and altered DNA damage response signatures suggestive of possible mechanisms of radioresistance. Further work is needed to understand how to overcome these molecular mechanisms of radiation resistance in MACROD2 deficient HPV+ HNSCC.