Targeting epigenetics using synthetic lethality in precision medicine

Technological breakthroughs in genomics have had a significant impact on clinical therapy for human diseases, allowing us to use patient genetic differences to guide medical care. The “synthetic lethal approach” leverages on cancer-specific genetic rewiring to deliver a therapeutic regimen that preferentially targets malignant cells while sparing normal cells. The utility of this system is evident in several recent studies, particularly in poor prognosis cancers with loss-of-function mutations that become “treatable” when two otherwise discrete and unrelated genes are targeted simultaneously. This review focuses on the chemotherapeutic targeting of epigenetic alterations in cancer cells and consolidates a network that outlines the interplay between epigenetic and genetic regulators in DNA damage repair. This network consists of numerous synergistically acting relationships that are druggable, even in recalcitrant triple-negative breast cancer. This collective knowledge points to the dawn of a new era of personalized medicine.