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Journal Of Modern Oncology[ISSN:1672-4992/CN:61-1415/R]

Issue:

2023 04

Page:

609-617

Research Field:

Publishing date:

Info

Title:

Integrated analysis of gastric cancer pharmacogenomic profiles

Author(s):

HAI Yanru; CAO Lihua; YU Huan; WU Jianmin

Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education,Beijing),Center for Cancer Bioinformatics,Peking University Cancer Hospital & Beijing Institute for Cancer Research,Beijing 100142,China.

Keywords:

gastric cancer; multi-omics analysis; drug sensitivity; bioinformatics; biomarkers

PACS:

R735.2

DOI:

10.3969/j.issn.1672-4992.2023.04.004

Abstract:

Objective:To investigate the predictive value of molecular characteristics of target genes for the sensitivity of the corresponding targeted drugs in gastric cancer (GC).Methods:We integrated the drug screening data and multi-omics molecular data of GC cell lines in six high-throughput datasets (GDSC1,GDSC2,CTRP v2,PRISM,CCLE and CCLE Proteomes),and systematically analyzed the correlations between the molecular characteristics of drug targets and the sensitivity of corresponding targeted compounds.We further evaluated the association between the molecular characteristics of the identified target genes and GC patient prognosis.Lastly,we verified the potential of predicted target genes as predictive biomarkers through siRNA knockdown and drug sensitivity experiments.Results:Based on the integrated analysis of multi-omics and drug screening data,we identified 15 target genes significantly associated with drug response of targeted compounds and GC patient prognosis,in which high expression of eight genes (PSMA3,XIAP,NUAK2,HDAC10,RRM2,MDM2,CHRNA2 and RRM1) and copy number amplification of six genes (HIPK3,HDAC8,SRC,FGFR1,MAGT1 and AR) were significantly associated with increased drug sensitivity to their targeted compounds and better patient outcome,while HSP90AB1 mutation was significantly associated with decreased drug sensitivity to the targeted compound HSP90 small molecule inhibitor NVP-AUY922 and worse prognosis.Through biological experiments,we further verified the predictive value of MDM2 expression level on the efficacy of its inhibitor nutlin-3a in gastric cancer.Conclusion:This analysis identified multiple potential biomarkers that could predict patient prognosis and the efficacy of targeted compounds,such HSP90AB1 mutation and MDM2 expression.Among them,the predictive effect of MDM2 expression has been verified by biological experiments,which provided clues for future clinical studies of their targeted drugs in GC.

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