Pharmacogenomic Analysis Of Sensitivity And Drug Resistance To PARP Inhibitors(Olaparib)

Background:DNA damage repair defects are one of the characteristics of certain malignancies.PARP inhibitors(Olaparib)are newly developed drugs for tumor cell DNA damage repair and its related pathways.In 2009,during a clinical trial,it first showed that it inhibits PARP 1,a key sensor of DNA damage,thus kills tumor cells;and it is closely related to BRCA1/2 gene mutation.This article summarizes the mechanism of action,clinical efficacy,and drug resistance of PARP inhibitors;and also discusses the use of PARP inhibitors to increase the opportunities of using precision medicine methods.Objective:The aim is using the pharmacogenomics technology to identify the genetic characteristics of human cancer cells that may increase or decrease sensitivity to Olaparib.The steps include the following: to explore the sensitivity and resistance of tumor cells to Olaparib;to obtain potential biomarkers;and use Olaparib in the treatment of a variety of tumors.Lastly,to guide future targeted therapy strategies and to provide a basis for clinical individualized treatment.Materials and methods:Based on the cell of the gene expression omics data and drug sensitivity results from the NCI-60 project(data from 9 different types of cancer tissues including breast cancer,central nervous system cancer,colon cancer,leukemia,melanoma,non-small cell lung cancer,ovarian cancer,prostate cancer,and kidney cancer),the mechanism of action and drug resistance of Olaparib are studied.First of all,using NCI-60 data analyze the significance of BRCA1/2 gene expression in drug sensitivity prediction(R package,Rcellminer).Next,based on the drug sensitivity results(IC50),divide tumor cell lines into two groups,PARP inhibitors sensitive groups and drug resistance,by selecting representative tumor cell lines in each group,(15 in the sensitive group and 22 in the drug-resistant group)(R package,Rcellminer).Then,perform the differential gene expression analysis(DGE)(GEO2R)to obtain the differential genes in the two groups.Finally,perform the protein-protein interactions(PPI)and functional enrichment analysis(STRing)on the up-regulated differential genes in order to find key nodes(key genes)and key molecular pathways.Results:The result of drug sensitivity data of Olaparib(NSC number 747856)in the NCI-60 tumor cell line;the expression characteristics of BRCA1/2 gene and its visual relationship with drug sensitivity;the full gene expression profiles of 15 sensitive cell lines,41 samples(drug activity> 0.5),22 resistant cell lines,and 65 samples(drug activity <-0.5),were obtained.Base on the comparing and analyzing of the differences of gene expression in the two groups,26 genes with high expression in the sensitive group and 5 genes with high expression in the drug resistance group was identified.The results of PPI analysis suggest that the proteins expressed by the differential genes in the sensitive group are biologically relevant;functional enrichment analysis(STRing)found that these up-regulated 26 genes are related to extracellular matrix,interstitial,collagen,etc.which may be sensitive to Olaparib Potential mechanisms;and resistance-related genes include F11 R,HHEX,ERBB3,GALNT12,SNX10.Conclusion:Identifying a genetic abnormality in a targeted pathway that is susceptible to drug abnormalities is the focus of targeted malignant tumor therapy.These highly expressed genes may become molecular markers of sensitivity to PARP inhibitors.This study explored the possibility of linking new effective genes to Olaparib.Pharmacogenomic analysis of pan-tumor cell lines has revealed many biomarkers that may be useful for patient stratification;it helps to achieve personalized treatment of PARP inhibitors in a variety of tumors.