Role of senescence induction in cancer treatment

Abstract

Cellular senescence is a form of permanent cell cycle arrest that can be triggered by a variety of cell-intrinsic and extrinsic stimuli, including telomere shortening, DNA damage, oxidative stress, and exposure to chemotherapeutic agents and ionizing radiation. Although the induction of apoptotic cell death is a desirable outcome in cancer therapy, mutations and/or deficiencies in the apoptotic signaling pathways have been frequently identified in many human cancer types, suggesting the importance of alternative apoptosis-independent therapeutic approaches for cancer treatment. A growing body of evidence has documented that senescence induction in tumor cells is a frequent response to many anticancer modalities including cyclin-dependent kinases 4/6 small molecule inhibitor-based targeted therapeutics and T helper-1 cytokine-mediated immunotherapy. This review discusses the recent advances and clinical relevance of therapy-induced senescence in cancer treatment.

Keywords: Cellular senescence; Cancer treatment; Chemotherapy; Ionizing radiation; Cyclin-dependent kinases 4/6 inhibitor; Aurora kinase inhibitor; Immunotherapy; T helper-1 cells; T helper-1 cytokines

Core tip: Both in vitro and in vivo studies have revealed that senescence induction in human cancer cells is a prominent response to chemotherapy and irradiation. A senescent phenotype has been detected in clinical tumor samples of breast cancer patients following preoperative neoadjuvant chemotherapy. Immunotherapy-induced senescence of cancer cells contributes to tumor regression in vivo. The induction of cancer cell senescence appears to be a major mechanism of action of cyclin-dependent kinases 4/6 small molecule inhibitor-based targeted therapy. Collectively, these preclinical and clinical observations have demonstrated an important role for senescence induction in cancer treatment.