mln-8237 and Papillomavirus-Infections

Human papilloma virus (HPV) is the main culprit in cancers of the cervix, penis, anus, skin, eye and head and neck. Current treatments for HPV cancers have not altered survival outcomes for 30 years and there is a significant lack of targeted therapeutic agents in the management of advanced HPV-related HNSCC. Here we show that survival and maintenance of HPV-positive HNC cells relies on the continuous expression of the major HPV oncogene, E7, and that Aurora kinases are critical for survival of high-risk HPV-positive HNC cells.. To assess the role of HPV E7 on HNC cell survival, RNA interference (RNAi) of the E7 gene was initially performed. Using an Aurora kinase inhibitor, Alisertib, the role of Aurora kinases in the carcinogenesis of HPV E7 positive HNC tumour lines was then investigated. An in vivo HNC xenograft model was also utilised to assess loss of tumour volume in response to RNAi E7 gene silencing and Alisertib treatment.. RNAi silencing of the HPV E7 gene inhibited the growth of HPV-positive HNC cells and in vivo tumour load. We show that HPV E7 oncogene expression confers sensitivity to Alisertib on HNC cells where Alisertib-mediated loss in in vitro cell viability and in vivo tumour load is dependent on E7 expression. Moreover, Aurora kinase inhibition induced degradation of MCL-1 in HPV E7-expressing HNC cells.. Overall, we show that Aurora kinases are a novel therapeutic target for HPV-positive HNCs. It might be feasible to combine Aurora kinase and MCL-1 inhibitors for future HNC therapies.

Topics: Animals; Apoptosis; Aurora Kinase A; Aurora Kinase B; Azepines; Female; Head and Neck Neoplasms; Human papillomavirus 16; Humans; Leupeptins; Mice; Myeloid Cell Leukemia Sequence 1 Protein; Papillomavirus E7 Proteins; Papillomavirus Infections; Proteolysis; Pyrimidines; RNA Interference; Xenograft Model Antitumor Assays

The activity and efficacy of Aurora inhibitors have been reported in a wide range of cancer types. The most prominent Aurora inhibitor is alisertib, an investigational Aurora inhibitor that has been the subject of more than 30 clinical trials. Alisertib has inhibitory activity against both Aurora A and B, although it is considered to be primarily an Aurora A inhibitor

Topics: Animals; Antineoplastic Agents; Aurora Kinase A; Aurora Kinase B; Azepines; Cell Line, Tumor; Disease Models, Animal; Female; Humans; Mice; Mitosis; Papillomaviridae; Papillomavirus Infections; Protein Kinase Inhibitors; Pyrimidines; Uterine Cervical Neoplasms; Xenograft Model Antitumor Assays