Drug resistance: origins, evolution and characterization of genomic clones and the tumor ecosystem to optimize precise individualized therapy

Progress in understanding and overcoming fatal intrinsic and acquired resistance is slow, with only a few exceptions. Despite advances in modern genome and transcriptome analysis, the controversy of the three different theories on drug resistance and tumor progression, namely dynamic intratumor heterogeneity, pre-existing minor genomic clones and tumor ecosystem, is unresolved. Moreover, evidence on transcriptional heterogeneity suggests the necessity of a drug bank for individualized, precise drug-sensitivity prediction. We propose a cancer type- and stage-specific clinicogenomic and tumor ecosystemic concept toward cancer precision medicine, focusing on early therapeutic resistance and relapse.