Modulation of the senescence response to delay accelerated aging in cancer therapy
Boshi Wang 1 , Simone Brandenburg 1 , Alejandra Hernandez-Segura 1 , Thijmen van Vliet 1 , Britt Sterken 1 , Coby Meijer 2 , Cornelis F. Calkhoven 1 , Jourik Gietema 2 and Marco Demaria 1
1 European Research Institute for the Biology of Ageing (ERIBA), University Medical Center Groningen (UMCG), University of Groningen (RUG); 2 Department of Medical Oncology, University Medical Center Groningen (UMCG), Groningen, Netherlands.
Most used anti-cancer therapeutic approaches are based on impairing mitosis and targeting highly proliferative cells. The non-specificity of these interventions often leads to short- and long-term side effects, and a general accelerated aging phenotype. Cellular senescence - a complex stress response whereby cells lose irreversibly their capacity to proliferate – is potent tumor suppressive mechanism and a desired outcome of anti-cancer therapies. Our data show that chemotherapy agents induce senescent cells in both mice and humans. However, chemotherapy-induced senescent cells develop a strong secretory phenotype (SASP) and contribute to chemotoxicity in mice including bone marrow suppression, cardiac decline, decreased physical activity and cancer relapse. Interestingly, chemotherapy treatment combined to genetic or pharmacological senolysis delays or prevents the onset of several pathologies. We also show that a novel class of oncological drugs -- the inhibitors of Cyclin- Dependent Kinases (CDK)-4/6 – induces a p53-mediated senescence program. Interestingly, using RNAseq, cytokine arrays and in-tissue analyses we demonstrate that CDKi-induced senescent cells are characterized by a strongly reduced SASP. CDKi-induced senescent cells fail to promote paracrine detrimental effects, and do not lead to adverse effects in mice. Together, our data suggest that modulating the senescence response is a potent strategy to limit the toxicity of ant-cancer treatments. This effect can be achieved either by eliminating detrimental senescent cells or by designing drugs that can promote irreversible growth arrest without strong paracrine effects. Importantly, the phenotypical characterization of these different senescent cells could predict toxicity and side effects associated to standard oncological drugs.
1 European Research Institute for the Biology of Ageing (ERIBA), University Medical Center Groningen (UMCG), University of Groningen (RUG); 2 Department of Medical Oncology, University Medical Center Groningen (UMCG), Groningen, Netherlands.
Most used anti-cancer therapeutic approaches are based on impairing mitosis and targeting highly proliferative cells. The non-specificity of these interventions often leads to short- and long-term side effects, and a general accelerated aging phenotype. Cellular senescence - a complex stress response whereby cells lose irreversibly their capacity to proliferate – is potent tumor suppressive mechanism and a desired outcome of anti-cancer therapies. Our data show that chemotherapy agents induce senescent cells in both mice and humans. However, chemotherapy-induced senescent cells develop a strong secretory phenotype (SASP) and contribute to chemotoxicity in mice including bone marrow suppression, cardiac decline, decreased physical activity and cancer relapse. Interestingly, chemotherapy treatment combined to genetic or pharmacological senolysis delays or prevents the onset of several pathologies. We also show that a novel class of oncological drugs -- the inhibitors of Cyclin- Dependent Kinases (CDK)-4/6 – induces a p53-mediated senescence program. Interestingly, using RNAseq, cytokine arrays and in-tissue analyses we demonstrate that CDKi-induced senescent cells are characterized by a strongly reduced SASP. CDKi-induced senescent cells fail to promote paracrine detrimental effects, and do not lead to adverse effects in mice. Together, our data suggest that modulating the senescence response is a potent strategy to limit the toxicity of ant-cancer treatments. This effect can be achieved either by eliminating detrimental senescent cells or by designing drugs that can promote irreversible growth arrest without strong paracrine effects. Importantly, the phenotypical characterization of these different senescent cells could predict toxicity and side effects associated to standard oncological drugs.
