Ultimate Precision: Targeting Cancer but Not Normal Self-replication.

Self-replication is the engine that drives all biologic evolution, including neoplastic evolution. A key oncotherapy challenge is to target this, the heart of malignancy, while sparing the normal self-replication mandatory for health and life. Self-replication can be demystified: it is activation of replication, the most ancient of cell programs, uncoupled from activation of lineage-differentiation, metazoan programs more recent in origin. The uncoupling can be physiologic, as in normal tissue stem cells, or pathologic, as in cancer. Neoplastic evolution selects to disengage replication from forward-differentiation where intrinsic replication rates are the highest, in committed progenitors that have division times measured in hours versus weeks for tissue stem cells, via partial loss of function in master transcription factors that activate terminal-differentiation programs (e.g., GATA4) or in the coactivators they use for this purpose (e.g., ARID1A). These loss-of-function mutations bias master transcription factor circuits, which normally regulate corepressor versus coactivator recruitment, toward corepressors (e.g., DNMT1) that repress rather than activate terminal-differentiation genes. Pharmacologic inhibition of the corepressors rebalances to coactivator function, activating lineage-differentiation genes that dominantly antagonize MYC (the master transcription factor coordinator of replication) to terminate malignant self-replication. Physiologic self-replication continues, because the master transcription factors in tissue stem cells activate stem cell, not terminal-differentiation, programs. Druggable corepressor proteins are thus the barriers between self-replicating cancer cells and the terminal-differentiation fates intended by their master transcription factor content. This final common pathway to oncogenic self-replication, being separate and distinct from the normal, offers the favorable therapeutic indices needed for clinical progress.