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.