MOLECULAR DRIVERS OF TUMOR HETEROGENEITY AND THERAPEUTIC RESISTANCE

Abstract

Heterogeneity of tumors and resistance to treatments is one of the greatest challenges to effective treatment of cancer and patient survival. Genetic, epigenetic, and transcriptional changes occurring continuously lead to the creation of heterogeneous cellular subpopulations within the same tumor microenvironment, which results in the heterogeneous nature of tumors. Such differences lead to variations in drug responsiveness, recurrence of the disease and targeted therapy failure. This research proposes to determine the drivers of tumor heterogeneity and therapeutic resistance with an integrated multi-omics methodology that uses transcriptomic and genomic profiling to understand the underlying biology. The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) publicly available datasets were studied to detect differentially expressed genes, somatic mutations, copy number variations, and dysregulated signaling pathways. The analysis of functional enrichment with Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) demonstrated that PI3K-AKT, MAPK, and p53 signaling pathways could play an important role in cancer progression and resistance to drugs. The analysis of protein-protein interaction network has identified some fundamental hub genes, TP53, MYC, AKT1, and CDK1, as the core regulators of tumor evolution and therapeutic failure. The results show that a concerted process of genomic changes and transcriptional reprogramming initiates tumor heterogeneity and underlines the importance of multi-target therapies. This combined system offers more understanding on the biology of cancer and aids in the creation of precision oncology-based treatments.