Therapeutic targeting of replicative immortality

摘要: One of the hallmarks malignant cell populations is ability to undergo continuous proliferation. This property allows clonal lineages acquire sequential aberrations that can fuel increasingly autonomous growth, invasiveness, and therapeutic resistance. Innate cellular mechanisms have evolved regulate replicative potential as a hedge against progression. When activated in absence normal terminal differentiation cues, these result state persistent cytostasis. state, termed “senescence,” be triggered by intrinsic processes such telomere dysfunction oncogene expression, exogenous factors DNA damaging agents or oxidative environments. Despite differences upstream signaling, senescence often involves convergent interdependent activation tumor suppressors p53 p16/pRB, but induced, albeit with reduced sensitivity, when are compromised. Doses conventional genotoxic drugs required achieve cancer much lower than doses outright death. Additional therapies, those targeting cyclin dependent kinases components PI3K signaling pathway, may induce specifically cells circumventing defects suppressor pathways exploiting cells’ heightened requirements for telomerase. Such treatments sufficient could provide increased patient survival fewer less severe side effects cytotoxic regimens. positive aspect countered important caveats regarding reversibility, genomic instability, paracrine increase heterogeneity adaptive resistance surviving cells. Nevertheless, effectively disrupt immortality will likely valuable new combinatorial approaches therapy.