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

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.
Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(© 2022 The Author(s).)