Induction of cell death represents a primary goal of most anticancer treatments. Despite the efficacy of such approaches, a small population of "persisters" develop evasion strategies to
therapy-induced cell death. While previous studies have identified mechanisms of resistance to apoptosis, the mechanisms by which persisters dampen other forms of cell death, such as pyroptosis, remain to be elucidated. Pyroptosis is a form of inflammatory cell death that involves formation of membrane pores, ion gradient imbalance, water inflow, and membrane
rupture. Herein, we investigate mechanisms by which
cancer persisters resist pyroptosis, survive, then proliferate in the presence of
tyrosine kinase inhibitors (TKI). Lung, prostate, and
esophageal cancer persister cells remaining
after treatments exhibited several hallmarks indicative of pyroptosis resistance. The inflammatory attributes of persisters included chronic activation of
inflammasome,
STING, and
type I interferons. Comprehensive metabolomic characterization uncovered that TKI-induced pyroptotic persisters display high
methionine consumption and excessive
taurine production. Elevated
methionine flux or exogenous
taurine preserved plasma membrane integrity via osmolyte-mediated effects. Increased dependency on
methionine flux decreased the level of one
carbon metabolism intermediate S-(5'-adenosyl)-L-homocysteine, a determinant of cell methylation capacity. The consequent increase in methylation potential induced
DNA hypermethylation of genes regulating
metal ion balance and intrinsic immune response. This enabled thwarting TKI resistance by using the hypomethylating agent
decitabine. In summary, the evolution of resistance to pyroptosis can occur via a stepwise process of physical acclimation and epigenetic changes without existing or recurrent mutations.
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