Crossroad between linear and nonlinear transcription concepts in the discovery of next-generation sequencing systems-based anticancer therapies

•Cancer genome evolution and tumor heterogeneity explain therapeutic resistance, relapse and death.•Standard single biopsy NGS and novel NGS applications empower intratumor and circulating genomic clone heterogeneity.•Dynamics of genomic clones-based intrapatient heterogeneity (IPH) shape two new horizons.•Targeting simple IPH with ‘linear’ transcription drugs is a realistic medium-term strategy.•Discovering comprehensive IPH and disrupting aberrant transcription biocircuits shapes future nonlinear therapy.

The unprecedented potential of standard and new next-generation sequencing applications and methods to explore cancer genome evolution and tumor heterogeneity as well as transcription networks in time and space shapes the development of next-generation therapeutics. However, biomedical and pharmaceutical research for overcoming heterogeneity-based therapeutic resistance is at an important crossroads. Focus on linear transcription-based drug development targeting dynamics of simple intrapatient structured genome diversity represents a realistic medium-term goal. By contrast, the discovery of nonlinear transcription drugs for targeting structural and functional genome and transcriptome heterogeneity represents a long-term rational strategy. This review compares effectiveness, challenges and expectations between linear and nonlinear drugs targeting simple intrapatient variation and aberrant transcriptional biocircuits, respectively.