Aurora A Is Critical for Survival in HPV-Transformed Cervical Cancer

Abstract

Human papillomavirus (HPV) is the causative agent in cervical cancer. HPV oncogenes are major drivers of the transformed phenotype, and the cancers remain addicted to these oncogenes. A screen of the human kinome has identified inhibition of Aurora kinase A (AURKA) as being synthetically lethal on the background of HPV E7 expression. The investigational AURKA inhibitor MLN8237/Alisertib selectively promoted apoptosis in the HPV cancers. The apoptosis was driven by an extended mitotic delay in the Alisertib-treated HPV E7-expressing cells. This had the effect of reducing Mcl-1 levels, which is destabilized in mitosis, and increasing BIM levels, normally destabilized by Aurora A in mitosis. Overexpression of Mcl-1 reduced sensitivity to the drug.The level of HPV E7 expression influenced the extent of Alisertibinduced mitotic delay and Mcl-1 reduction. Xenograft experiments with three cervical cancer cell lines showed Alisertib inhibited growth of HPV and non-HPV xenografts during treatment. Growth of non-HPV tumors was delayed, but in two separate HPV cancer cell lines, regression with no resumption of growth was detected, even at 50 days after treatment. A transgenic model of premalignant disease driven solely by HPV E7 also demonstrated sensitivity to drug treatment. Here, we show for the first time that targeting of the Aurora A kinase in mice using drugs such as Alisertib results in a curative sterilizing therapy that may be useful in treating HPV-driven cancers.

Inhibition of Aurora A and Aurora B Is Required for the Sensitivity of HPV-Driven Cervical Cancers to Aurora Kinase Inhibitors

“…Cell culture and siRNA transfection HPV-positive cervical cancer cell lines HeLa, CaSki, HPVnegative C33A (cervix), and SCC25 (tongue SCC) were cultured as described previously (9). HPV16 E6/E7 transformed Ect1/ E6E7 and VK2/E6E7 cell lines are of ectocervical and vaginal tissue origins, respectively, and CaSki cells were obtained from the ATCC.…”

“…SiRNAs were transfected into HeLa cells by reverse transfection as described previously (14). Dose response assays were performed in 384-well plate format using resazurin cell viability assay as a readout (9).…”

“…In previous work we have reported that Aurora A and B were identified as synthetic lethal hits with HPV E7 expression in cervical cancer, and that the investigational Aurora A inhibitor alisertib displayed selectivity for the HPV-dependent cervical cancers in vitro and in xenograft models (9). Alisertib has been reported to be primarily an Aurora A inhibitor, although it inhibits Aurora B at higher doses in vitro (2,10,11).…”

The Therapeutic Potential of CRISPR/Cas9 Systems in Oncogene-Addicted Cancer Types: Virally Driven Cancers as a Model System

“…The 5-year survival rate has not changed for 20 years, so current treatment strategies have plateaued in efficacy 12 . Vaccines cannot treat already-established cancer nor do they provide protection against all types of human papillomavirus (HPV) infection 11, 13, 14. Moreover, current strategies (radiotherapy, chemotherapy, and surgery) suffer from serious drawbacks, are harsh on normal cells, and have not shown adequate selectivity in targeting the malignant tissue of the cervix 12, 15, 16, 17, 18…”

DNA replication licensing factor MCM2, geminin, and Ki67 define proliferative state and are linked with survival in oral squamous cell carcinoma

“…Replication‐licensing proteins and mitotic kinases have been exploited as novel markers of growth in primary diagnosis, surveillance, and prognosis in numerous tumour types, including bladder, cervix, prostate, and in other cancers . Yet, multiparameter analysis of cell‐cycle kinetics in oral squamous cel carcinoma (OSCC) have not been carried out, and the prognostic role of replication licensing and mitotic machinery proteins in OSCC needs further validation.…”