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

doi:10.1016/j.csbj.2022.09.025

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

Comput Struct Biotechnol J. 2022 Sep 21:20:5287-5295. doi: 10.1016/j.csbj.2022.09.025. eCollection 2022.

Authors

Hsih-Te Yang¹, Ming-Yu Chien², Jung-Hsien Chiang^{2

3}, Peng-Chan Lin^{4

5}

Affiliations

¹ Levine Cancer Institute, Atrium Health, Charlotte, NC 28204, USA.
² Department of Computer Science and Information Engineering, College of Electrical Engineering and Computer Science, National Cheng Kung University, Tainan 704, Taiwan.
³ Institute of Medical Informatics, National Cheng Kung University, Tainan 704, Taiwan.
⁴ Department of Oncology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan.
⁵ Department of Genomic Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan.

Abstract

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 ( $S_{g}$ ) 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.

Keywords: S g , essential gene score; S t , trigger term score; BC, breast cancer; CD82; Colorectal cancer; DAISY, data mining synthetic lethality identification pipeline; HTS, high-throughput screening; High-throughput screening; KRAS mutation; MSI-H, microsatellite instability; NLP, natural language processing; PARP, poly (ADP-ribose) polymerase; SL, synthetic lethality; Text-mining; WRN, Werner syndrome helicase.