Subjugation of TGFβ Signaling by Human Papilloma Virus in Head and Neck Squamous Cell Carcinoma Shifts DNA Repair from Homologous Recombination to Alternative End-Joining

Abstract

Purpose: Following cytotoxic therapy, 70% of patients with human papillomavirus (HPV) positive oropharyngeal head and neck squamous cell carcinoma (HNSCC) are alive at 5 years compared to 30% of those with similar HPV-negative cancer, which is thought to be due to dysregulation of DNA repair. Loss of transforming growth factor {beta} (TGF{beta}) signaling is a poorly studied consequence of HPV that could contribute to this phenotype.\n\nExperimental Design: Human HNSCC cell lines (n=9), patient-derived xenografts (n=9), tissue microarray (n=194), TCGA expression data and primary tumor specimens (n=10) were used to define the relationship between TGF{beta} competency, response to DNA damage, and type of DNA repair.\n\nResults: Analysis of HNSCC specimens in situ and in vitro showed that HPV associates with loss of TGF{beta} signaling that increases the response to radiation or cisplatin. TGF{beta} suppressed miR-182 that inhibited both BRCA1, necessary for homologous recombination repair, and FOXO3, which is required for ATM kinase activity. TGF{beta} signaling blockade by either HPV or inhibitors released this control, compromised HRR and increased response to PARP inhibition. Antagonizing miR-182 rescued the homologous recombination deficit in HPV+ cells. Loss of TGF{beta} signaling unexpectedly increased error-prone, alternative end-joining repair.\n\nConclusions: HPV-positive HNSCC cells are unresponsive to TGF{beta}. Abrogated TGF{beta} signaling compromises homologous recombination and shifts reliance on alt-EJ repair that provides a mechanistic basis for sensitivity to PARP inhibitors. The effect of HPV in HNSCC provides critical validation of TGF{beta}s role in DNA repair proficiency and further raises the translational potential of TGF{beta} inhibitors in cancer therapy.