Literature-based translation from synthetic lethality screening into therapeutics targets: CD82 is a novel target for KRAS mutation in colon cancer

Hsih Te Yang, Ming Yu Chien, Jung Hsien Chiang, Peng Chan Lin

研究成果: Article同行評審

1 引文 斯高帕斯(Scopus)

摘要

Synthetic lethality (SL) is an emerging therapeutic paradigm in cancer. We introduced a different approach to prioritize SL gene pairs through literature mining and RAS-mutant high-throughput screening (HTS) data. We matched essential genes from text-mining and mutant genes from the COSMIC and CCLE HTS datasets to build a prediction model of SL gene pairs. CCLE gene expression data were used to enrich the essential-mutant SL gene pairs using Spearman's correlation coefficient and literature mining. In total, 223 essential trigger terms were extracted and ranked. The threshold of the essential gene score (Sg) was set to 10. We identified 586 genes essential for the SL prediction model of colon cancer. Seven essential RAS-mutant SL gene pairs were identified in our model, including CD82-KRAS/NRAS, PEBP1-NRAS, MT-CO2-HRAS, IFI27-NRAS/KRAS, and SUMO1-HRAS gene pairs. Using RAS-mutant HTS data validation, we identified two potential SL gene pairs, including the CD82 (essential gene)–KRAS (mutant gene) pair and CD82–NRAS pair in the DLD-1 colon cancer cell line (Spearman's correlation p-values = 0.004786 and 0.00249, respectively). Based on further annotations by PubChem, we observed that digitonin targeted the complex comprising CD82, especially in KRAS-mutated HCT116 cancer cells. Moreover, we experimentally demonstrated that CD82 exhibited selective vulnerability in KRAS-mutant colorectal cancer. We used literature mining and HTS data to identify candidates for SL targets for RAS-mutant colon cancer.

原文English
頁(從 - 到)5287-5295
頁數9
期刊Computational and Structural Biotechnology Journal
20
DOIs
出版狀態Published - 2022 1月

All Science Journal Classification (ASJC) codes

  • 生物技術
  • 生物物理學
  • 結構生物學
  • 生物化學
  • 遺傳學
  • 電腦科學應用

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