Image Evaluation Of Heterogeneous Response To Treatment And Exploration Of Potential Target And Mechanism Of Traditional Chinese Medicine Treatment Based On Network Pharmacology Analysis In Lung Adenocarcinoma

Objective:In the first part of this study,the imaging evaluation model of lung adenocarcinoma tumor treatment heterogeneity is constructed,and the correlation between the heterogeneity of imaging evaluation and clinicopathological characteristics,prognosis,treatment efficacy,genome and TCM syndrome types is explored.In the second part,we explored the potential targets and mechanism of Huangqi,Beisashen and Nansashen in the treatment of lung adenocarcinoma.Explore whether they have potential clinical application prospects in interfering with lung cancer gland heterogeneity.Methods:For the first part,we infer the intratumoral heterogeneity of TCGA pancarcinoma to determine the level of tumor heterogeneity of lung adenocarcinoma by ABSOLUTE software.We included 49 patients with advanced lung adenocarcinoma before treatment.All patients have a thin layer of no less than 2 nodules(thickness of axial image layer is 1mm)CT enhanced scan image and gene sequencing data.Clinicians and imaging doctors jointly determined the target lesion and used single-path measurement to quantify the lesion.The efficacy evaluation follows the solid tumor efficacy evaluation standard(RECIST).We recorded the percentage change of each target lesion from the baseline valued as the change parameter.The Coefficient of Variation(CV)of each change parameter is counted as the patient's final tumor heterogeneity index.We then collected patients' TCM syndrome types and genomic characteristics for correlation research.In the second part,based on the pharmacology database of the traditional Chinese medicine system,we obtained the chemical constituents of Huangqi,Beisashen and Nansashen and their corresponding targets.The R package limma was used to identify differential genes.We used Cytoscape software to construct and visualized the "drug-component-target-disease" network.The STRING website was used to build protein interaction networks.We performed GO enrichment analysis and KEGG pathway analysis of the target through the biological information annotation database.Results:Analysis of 33 types of TCGA pan-cancer population found that among all types of cancer,lung adenocarcinoma has the highest degree of intratumoral heterogeneity.We established a tumor heterogeneity imaging evaluation system based on RECIST efficacy evaluation system,and constructed a heterogeneous prognosis model.At the optimal cut-off point,the prognosis of patients with high heterogeneity is worse than that with lower heterogeneity(PFS: HR:4.27,95% CI: 1.59-11.51,P = 0.001).CV has good prediction accuracy(AUC = 0.77).Univariate and multivariate Cox analysis showed that CV is an independent prognostic factor.In the association study with the genome,patients with high heterogeneity have a higher tumor mutation burden.In addition,patients with high heterogeneity were significantly associated with both Qi and Yin deficiency syndromes(P < 0.001,Fisher's exact test).In the compatibility of Huangqi,Beisashen and Nansashen,we have identified 13 active ingredients and 22 target genes.These molecules are considered as potential therapeutic targets for advanced lung adenocarcinoma.The main pathways of target genes include response to reactive oxygen species,transforming growth factor beta activation,DNA damage response,p53-like mediator signal transduction leading to cell cycle arrest,p53 signaling pathway,transcriptional dysregulation in cancer,IL-17 signaling pathway,Proteoglycan regulation in cancer.Among them,6 genes may be closely related genes with heterogeneous regulation(ADRB2,PLAU,COL1A1,NQO1,COL3A1 and IGFBP3).Conclusions:We have established an imaging evaluation system for tumor treatment response heterogeneity,and the Coefficient of Variation(CV)is significantly associated with poor prognosis.Patients with high heterogeneity often show features such as poor prognosis,high tumor mutation burden,and deficiency of both Qi and Yin.In addition,we have identified potential targets and mechanisms of action related to the treatment of lung adenocarcinoma from Huangqi,Nansashen and Beisashen.Some targets may be closely related to heterogeneous regulation.