TY - JOUR
T1 - Literature-based translation from synthetic lethality screening into therapeutics targets
T2 - CD82 is a novel target for KRAS mutation in colon cancer
AU - Yang, Hsih Te
AU - Chien, Ming Yu
AU - Chiang, Jung Hsien
AU - Lin, Peng Chan
N1 - Funding Information:
Funding: This work was supported in part by the Ministry of Science and Technology (MOST) , Taiwan, under Research Grant of MOST 111-2634-F-006-002 , MOST 111-2634-F-006-007 , and MOST 110-2634-F-006-020 , Ministry of Health and Welfare ( MOHW111-TDU-B-221-014005 ), and National Cheng Kung University Hospital ( NCKUH-11102061 ).
Publisher Copyright:
© 2022 The Author(s)
PY - 2022/1
Y1 - 2022/1
N2 - 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.
AB - 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.
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U2 - 10.1016/j.csbj.2022.09.025
DO - 10.1016/j.csbj.2022.09.025
M3 - Article
AN - SCOPUS:85138399380
SN - 2001-0370
VL - 20
SP - 5287
EP - 5295
JO - Computational and Structural Biotechnology Journal
JF - Computational and Structural Biotechnology Journal
ER -