Assessing the Complexities of Utilizing BH3 Mimetics for a Senolytic Strategy in Combination with Ionizing Radiation

Radiation-induced senescence (RIS) is thought to be one mechanism by which tumor cells can survive radiation-induced cell death. Accumulating evidence suggests that therapy-induced senescence (TIS) (triggered by both chemotherapy and/or irradiation) also facilitates tumor cell recovery, thereby contributing to disease recurrence. Furthermore, the factors secreted by senescent tumor cells (the senescence-associated secretory phenotype (SASP)) have, in some cases, been reported to be tumor-promoting, immunosuppressive, and potentially responsible for some of the adverse effects of radiation. Given these largely undesirable attributes of RIS in tumor cells, the use of senolytic agents to eliminate senescent tumor cells has been investigated in preclinical studies. An analysis of the available literature on RIS in cell culture models tends to support the utility of the Bcl-xL/Bcl-2/Bcl-w-targeting agent ABT-263 (navitoclax), in combination with a single high-dose of radiation and, in some cases, with fractionated irradiation. However, because drug action has also been reported when administered prior to irradiation, prior tumor cell entry into senescence may not be obligatory for enhancement of radiation sensitivity by ABT-263. This conclusion is also consistent with drug action against tumor cells with low RIS levels, such as those induced by fractionated irradiation. While a relatively small number of studies in tumor-bearing animals demonstrate the effectiveness of ABT-263 in combination with radiation in vivo, once the drug pressure has been relaxed, the tumor cells likely still retain the capacity to recover proliferative capacity. Since ABT-263 is unlikely to be approved for the clinical treatment of solid tumors due to both on-target (thrombocytopenia) and off-target (neutropenia) toxicities, the few studies indicating improved radiosensitivity with ABT-199 (venetoclax) are intriguing, suggesting that targeting of Bcl-xL may not be a strict requirement for the combination strategy. Finally, it is worth noting that senolytic agents have the potential to protect normal tissue from radiation-induced damage, which may prove to be the most clinically relevant observation for this class of drugs.