Translational Cancer Biology Research Unit, Cancer Research Malaysia, Cancer Research Malaysia, 2nd Floor Outpatient Center, Subang Jaya Medical Center, No. 1, Jalan SS12/1A, 47500, Subang Jaya, Selangor, Malaysia.
Department of Biostatistics and Bioinformatics, Moffitt Cancer Center, Tampa, FL, USA.
Sci Rep. 2021 Dec 14;11(1):23933. doi: 10.1038/s41598-021-03418-1.
Effective treatment options for head and neck squamous cell carcinoma (HNSCC) are currently lacking. We exploited the drug response and genomic data of the 28 HNSCC cell lines, screened with 4,518 compounds, from the PRISM repurposing dataset to uncover repurposing drug candidates for HNSCC. A total of 886 active compounds, comprising of 418 targeted cancer, 404 non-oncology, and 64 chemotherapy compounds were identified for HNSCC. Top classes of mechanism of action amongst targeted cancer compounds included PI3K/AKT/MTOR, EGFR, and HDAC inhibitors. We have shortlisted 36 compounds with enriched killing activities for repurposing in HNSCC. The integrative analysis confirmed that the average expression of EGFR ligands (AREG, EREG, HBEGF, TGFA, and EPGN) is associated with osimertinib sensitivity. Novel putative biomarkers of response including those involved in immune signalling and cell cycle were found to be associated with sensitivity and resistance to MEK inhibitors respectively. We have also developed an RShiny webpage facilitating interactive visualization to fuel further hypothesis generation for drug repurposing in HNSCC. Our study provides a rich reference database of HNSCC drug sensitivity profiles, affording an opportunity to explore potential biomarkers of response in prioritized drug candidates. Our approach could also reveal insights for drug repurposing in other cancers.
目前缺乏对头颈鳞状细胞癌（HNSCC）有效的治疗选择。我们利用来自 PRISM 再利用数据集的 28 种 HNSCC 细胞系的药物反应和基因组数据，对 4518 种化合物进行筛选，以发现用于 HNSCC 的再利用药物候选物。共鉴定出 886 种活性化合物，包括 418 种靶向癌症化合物、404 种非肿瘤学化合物和 64 种化疗化合物，用于 HNSCC。靶向癌症化合物中作用机制的主要类别包括 PI3K/AKT/MTOR、EGFR 和 HDAC 抑制剂。我们已经为 HNSCC 的再利用筛选了 36 种具有丰富杀伤活性的化合物。综合分析证实，EGFR 配体（AREG、EREG、HBEGF、TGFA 和 EPGN）的平均表达与奥希替尼的敏感性相关。还发现与免疫信号和细胞周期相关的新的潜在反应生物标志物与对 MEK 抑制剂的敏感性和耐药性分别相关。我们还开发了一个 RShiny 网页，以促进交互式可视化，为 HNSCC 的药物再利用进一步产生假说。我们的研究为 HNSCC 的药物敏感性概况提供了丰富的参考数据库，为探索优先药物候选物中的潜在反应生物标志物提供了机会。我们的方法还可以为其他癌症的药物再利用提供启示。
