Spatiotemporal diversification of intrapatient genomic clones and early drug development concepts realize the roadmap of precision cancer medicine

•Molecular pathology orchestrating therapeutic resistance remains poorly understood.•Validity of NGS to identify IPH enables overcoming of intrinsic and acquired resistance.•The dynamics of IPH shape a new era in the discovery of biomarkers and oncotargets.•Early drug discovery strategy could predict FDA approval.•The spatiotemporal IPH concept will substantially contribute to precision oncology. The unmet clinical needs of high relapse and cancer-related death rates are reflected by the poor understanding of the genome-wide mutational landscape and molecular mechanisms orchestrating therapeutic resistance. Emerging potential solutions to this challenge include the exploration of cancer genome dynamic evolution in time and space. Breakthrough next-generation sequencing (NGS) applications including multiregional NGS for intratumor heterogeneity identification, repeated cell-free DNA/circulating tumor DNA-NGS for detecting circulating genomic subclones and their comparison to reveal intrapatient heterogeneity (IPH) could identify the dynamic emergence of resistant subclones in the neoadjuvant, adjuvant and metastatic setting. Based on genome-phenotype map, and potential promising findings, rigorous evaluation of IPH spatiotemporal evolution and early drug development concepts in innovative clinical trials could dramatically speed up the translational process to achieve clinical precision oncology. Understanding and identifying the dynamic emergence of the druggable mutational and molecular landscape in response to therapy following Darwinian evolution creates the foundation of precision oncology to overcome therapeutic resistance.