Abstract 368: Aurora kinase inhibitors cause cell death in HPV+ cells: A plausible treatment option for HPV+ cancers
Academic Article
Overview
Research
Identity
Additional Document Info
Other
View All
Overview
abstract
AbstractHuman papilloma virus (HPV) driven cancers are common and lethal. The standard of care chemo-radiation treatment for HPV+ head and neck squamous cell carcinoma (HNSCC) results in permanent, often life-altering, toxicities in a relatively young population (aged ~45-55). Additionally, those who recur have poor outcomes. Therefore, there is an urgent need for better treatment options. No biomarker-driven targeted therapies are available. To address the current unmet need, we hypothesized that a large-scale High Throughput Drug Screen (HTDS) comparing drug efficacy in HPV+ and HPV- cell lines would identify biomarker driven, effective and less toxic options for HPV+ cancers. We tested the drug- sensitivity of 864 unique drugs (0-3.1 M) in 51 classes based on their targets in 16 HPV+ and 17 HPV- squamous cancer cell lines. Cells were treated for 72 hours and DAPI+ nuclei counted before and after drug treatment. We used the Area Over the Curve_Lethal Dose (AOC_LD) to measure drug sensitivity because it is independent of cell division. We defined effective drugs as those that led to cell death (i.e., less cells at the end of drug treatment than prior to treatment) in at least one cell line. About half of the drugs tested (439) were effective and certain classes of drugs were enriched in either the effective or ineffective categories (Pearson residual). We found that Aurora kinase inhibitors were the most effective class overall. Other effective drug classes included anthracyclines, vinca-alkaloids, and inhibitors of HDAC, proteasome, EGFR, CDC7, and BTK1. Only 30 drugs had a differential effect based on HPV status. All 16 Aurora kinase inhibitors were more effective in HPV+ than in HPV- cells and the difference in sensitivity (dichotomous variable) was statistically significant in 7 of them. To determine if factors other than HPV status predict response to Aurora kinase inhibitors, we compared the expression of 304 proteins (RPPA) and mutational status for the 50 most commonly mutated genes in HNSCC to drug efficacy. The expression of eight proteins were associated with sensitivity to multiple Aurora kinase inhibitors. We validated RPPA data by immunoblotting and observed that only Rb, pRB(S807/811) and p16 correlated with drug sensitivity. For gene mutations, only TP53 mutations correlated with drug resistance with 7 Aurora kinase inhibitors. Interestingly, these two biomarkers, Rb and TP53, corroborate well with HPV status. To validate the screening results, we treated HPV+ cells with two clinically relevant Aurora kinase inhibitors, alisertib and barasertib, and observed significantly more cell death in HPV+ cells in comparison with HPV- cells. Therefore, our present study portrays Aurora kinase inhibitors as an effective strategy for HPV+ cancer cells. Multiple Aurora kinase inhibitors are currently in clinical development making the clinical application of our data possible soon.Citation Format: Tuhina Mazumdar, Li Shen, Wei Xu, Soma Ghosh, Reid T. Powell, Clifford Stephan, Curtis R. Pickering, Jeffery N. Myers, Jing Wang, Faye M. Johnson. Aurora kinase inhibitors cause cell death in HPV+ cells: A plausible treatment option for HPV+ cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 368.
