Anastasis, recovery from the brink of death as a mechanism of drug resistance

Abstract As a major mechanism of action, many types of cancer therapy induce apoptosis in cancer cells. Apoptosis is a highly conserved form of regulated cell death that functions to remove excess or damaged cells in response to cellular stress. Apoptotic cells exhibit stereotypic morphological changes that result from biochemical activation of caspases. Activation of executioner caspases is a necessary step during apoptosis and is widely regarded as a biochemical “point of no return.” However, recent evidence suggests that cells can recover from apoptosis upon removal of the stress through a process called anastasis. Anastasis (Greek for “rising to life”) is defined as the recovery of cells from the brink of apoptotic cell death and is a process by which cells survive executioner caspase activation following transient exposure to a lethal dose of an apoptotic stimulus. Since radio- and chemotherapy, and targeted therapies are often administered at high doses transiently, anastasis may represent a survival mechanism that occurs in a subset of cancer cells, leading to chemoresistance and cancer recurrence. Recovery of cells after caspase activation can also result in genetic instability and increased mutational load, and leads to proliferation and migration, suggesting that anastasis may contribute to tumor progression and metastasis, in addition to drug resistance. In this chapter, we will review recent advances in understanding molecular mechanisms underlying anastasis in cancer cells and discuss emerging strategies for suppressing this response during cancer treatment.