Mechanisms of Resistance to Cell Death Pathways in Cancer Cells

Resistance to cell death often hampers anticancer therapies. Such resistance can arise during tumor development or during the treatment of cancer, when cells escape the natural or therapy-evoked cell death. They escape death by acquiring genetic or epigenetic alterations that disrupt the normal cell death pathways. These cell death pathways switch on a cell-intrinsic suicide program, termed apoptosis, whose key components are a family of proteases, the caspases. Caspase activity is controlled by activating or inhibiting proteins that are subject to regulation by two major pathways. The intrinsic pathway emanates from mitochondria and is regulated by proteins of the BCL-2 family. The extrinsic pathway is initiated by membrane-bound death receptors. Inhibitor of apoptosis proteins and heat shock proteins further modulate the execution of the apoptotic program. Knowledge about cancer-specific alterations of these pathways has paved the way for novel therapeutic approaches to overcome resistance to cell death.