Synthetic lethal metabolic targeting of cellular senescence in cancer therapy

In mice with Eµ- myc transgenic lymphomas in which therapy-induced senescence (TIS) depends on the H3K9 histone methyltransferase Suv39h1, TIS-competent lymphomas but not TIS-incompetent Suv39h1 – lymphomas show increased glucose utilization and ATP production after senescence-inducing chemotherapy to cope with proteotoxic stress elicited by factors of the senescence-associated secretory phenotype (SASP); senescent cancers are selectively vulnerable to drugs that block glucose utilization or autophagy. Senescent cancer cells as secondary drug targets Cytotoxic therapy can induce cellular senescence, a desirable outcome as it halts the uncontrolled proliferation of cancer cells. Less desirable is the build-up of senescent cells. Working with a mouse lymphoma model, Clemens Schmitt and colleagues show that an increased dependence on metabolic processes makes chemotherapy-induced senescent cells selectively vulnerable to drugs that block glucose utilization or autophagy. Both genetic and pharmacological blockade of glucose metabolism prompt tumour regression and improve survival in the mouse model, suggesting that targeted combination therapies may be of value in patients with lymphomas and possibly other cancers in which cancer cells undergo chemotherapy-induced senescence. Activated oncogenes and anticancer chemotherapy induce cellular senescence, a terminal growth arrest of viable cells characterized by S-phase entry-blocking histone 3 lysine 9 trimethylation (H3K9me3) 1 , 2 . Although therapy-induced senescence (TIS) improves long-term outcomes 3 , potentially harmful properties of senescent tumour cells make their quantitative elimination a therapeutic priority. Here we use the Eµ- myc transgenic mouse lymphoma model in which TIS depends on the H3K9 histone methyltransferase Suv39h1 to show the mechanism and therapeutic exploitation of senescence-related metabolic reprogramming in vitro and in vivo . After senescence-inducing chemotherapy, TIS-competent lymphomas but not TIS-incompetent Suv39h1 – lymphomas show increased glucose utilization and much higher ATP production. We demonstrate that this is linked to massive proteotoxic stress, which is a consequence of the senescence-associated secretory phenotype (SASP) described previously 4 , 5 , 6 . SASP-producing TIS cells exhibited endoplasmic reticulum stress, an unfolded protein response (UPR), and increased ubiquitination, thereby targeting toxic proteins for autophagy in an acutely energy-consuming fa