Receptor-interacting protein kinase-3 (RIP3, or RIPK3) is an essential part of the cellular machinery that executes “programmed”, or “regulated”, necrosis. Here we show that programmed necrosis is activated in response to many chemotherapeutic agents and contributes to chemotherapy-induced cell death. However, we show RIP3 expression is often silenced in cancer cells due to genomic methylation near its transcriptional start site, so RIP3-dependent activation of MLKL and downstream programmed necrosis during chemotherapeutic death is largely repressed. Nevertheless, treatment with hypomethylating agents restores RIP3 expression, and thereby promotes sensitivity to chemotherapeutics in a RIP3-dependent manner. RIP3 expression is reduced in tumors when compared to normal tissue in 85% of breast cancer patients, suggesting that RIP3 deficiency is selected for during tumor growth/development. Since hypomethylating agents are reasonably well-tolerated in patients, we propose that RIP3-deficient cancer patients may benefit from receiving hypomethylating agents to induce RIP3 expression prior to treatment with conventional chemotherapeutics.
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