Targeting Senescent Cells to Better Address Cancer and Consequences of Cancer Therapy
The goal of cancer therapies is to kill cancerous cells or force those cells into the state of senescence, to shut down their uncontrolled replication. Chemotherapy and radiotherapy do harm non-cancerous cells as well, however, and can create further senescent cells in this way. It is thought that a substantial fraction of the increased mortality and risk of age-related disease seen in cancer survivors is due to the increased burden of senescent cells produced by the treatment of cancer. That is obviously preferential to death by cancer, but it is a concern, with a significant negative impact to remaining life expectancy. With the advent of senolytic therapies capable of selectively destroying senescent cells, it seems likely that this further harm inflicted on cancer patients can be ameliorated, however.
Cellular senescence is an inherent and virtually unavoidable consequence of treatment in patients with cancer. Cancer cell senescence mainly refers to surviving cancer cells that enter stable and durable cell cycle arrest, but can also be triggered in non-malignant cells in various organ systems across the body. Given the complex cell-extrinsic effects that senescent cells can exert in their surroundings, and the fundamental cell-intrinsic rewiring that profoundly alters cellular functionality and can account for stem-like reprogramming, the consequences of senescence are far more complex than those of apoptosis. Thus, managing residual senescent cancer cells as well as the consequences of senescence of non-malignant cells in patients receiving pro-senescent antitumour therapies is a clinical challenge.
Weighing the balance between the 'bright' and 'dark' sides of senescence is difficult, given that tumour-suppressive and tumour-promoting effects linked to senescent cancer cells can coexist in the same patient. Specifically, neither a dependable quantitative assessment of the different contributions that such effects could have on long-term outcome nor marker-based detection and selective targeting of less-desirable senescent cell populations is currently feasible in the clinic. Pharmacological suppression or modulation of the senescence-associated secretory phenotype (SASP) might work to a certain extent, but is unlikely to robustly change tumour fate. By and large, premature cancer cell senescence has acutely beneficial but chronically detrimental ramifications.
Most cytotoxic and cytostatic cancer treatments currently available induce senescence, whether intended or not, as a collateral effect in a certain proportion of the surviving cancer cell population. Thus far, senolysis (that is, senescence-related opportunities to eliminate drug-exposed malignant cells that failed to undergo apoptotic cell death in the first place but contributed to the initial treatment response via proliferative arrest) seems to be the preferred strategy because it seems the only definitive option towards tumour eradication. Although numerous promising candidate senolytics are being identified, some of which have entered clinical trials, prospective results of large-cohort oncology trials remain to be reported. Such studies should provide insights as to whether protection from post-senescent cancer relapse and concurrent elimination of organ function-disabling senescent cells in non-malignant tissues can be established as key objectives of therapeutic senolytic approaches in patients with cancer.