Clearance of therapy‐induced senescent tumor cells by the senolytic ABT‐263 via interference with BCL‐X_L–BAX interaction

Abstract

Tumor cells undergo senescence in response to both conventional and targeted cancer therapies. The induction of senescence in response to cancer therapy can contribute to unfavorable patient outcomes, potentially including disease relapse. This possibiliy is supported by our findings that tumor cells induced into senescence by doxorubicin or etoposide can give rise to viable tumors in vivo. We further demonstrate sensitivity of these senescent tumor cells to the senolytic ABT-263 (navitoclax), therefore providing a "two-hit" approach to eliminate senescent tumor cells that persist after exposure to chemotherapy or radiation. The sequential combination of therapy-induced senescence and ABT-263 could shift the response to therapy toward apoptosis by interfering with the interaction between BCL-X L and BAX. The administration of ABT-263 after either etoposide or doxorubicin also resulted in marked, prolonged tumor suppression in tumorbearing animals. These findings support the premise that senolytic therapy following conventional cancer therapy may improve therapeutic outcomes and delay disease recurrence.

Senolytics for Cancer Therapy: Is All that Glitters Really Gold?

“…Clearance of senescent tumor cells by navitoclax has been reported to enhance tumor regression/control and increase mouse survival [27,50,143]. As in non-tumor models, the senolytic activity of ABT-263 appears to depend upon inhibition of BCL-X L [27,50]. Further, our laboratory has recently reported that BAX, but not BAK, is required for cell killing by ABT-263 [27].…”

“…As in non-tumor models, the senolytic activity of ABT-263 appears to depend upon inhibition of BCL-X L [27,50]. Further, our laboratory has recently reported that BAX, but not BAK, is required for cell killing by ABT-263 [27]. However, in a recent publication with irradiated soft-tissue sarcoma, BCL-2 inhibition, albeit using supraclinical concentrations of ABT-199, was sufficient to promote senolysis, demonstrating the complex heterogeneity in which BCL-2 family member proteins senescent tumor cells depend upon for survival [146].…”

“…In established malignancies undergoing treatment, a plethora of anti-cancer drugs with variable mechanisms of action have been shown to promote a form of therapy-induced senescence (TIS) both in vitro and in vivo [24]. For example, conventional therapies such as etoposide, doxorubicin, and cisplatin are established inducers of TIS [25][26][27][28][29][30]. Targeted therapies, such as the BRAF inhibitor vemurafenib, EGFR inhibitor osimertinib, and hormonal therapies, including fulvestrant and androgen deprivation, have also been shown to result in senescence induction [31][32][33][34][35][36][37][38].…”

“…Navitoclax has shown a remarkable capacity to eliminate tumor cells induced into senescence by a variety of therapies, including lung and melanoma cells treated with aurora kinase inhibitors or etoposide [142]; lung cancer cells treated with etoposide or radiation [27]; breast cancer cells treated with doxorubicin, radiation, or BET inhibitors [27,143,144]; ovarian cancer cells treated with PARP inhibitors [50]; and prostate tumor cells treated with PARP inhibitors or radiation [145]. Clearance of senescent tumor cells by navitoclax has been reported to enhance tumor regression/control and increase mouse survival [27,50,143]. As in non-tumor models, the senolytic activity of ABT-263 appears to depend upon inhibition of BCL-X L [27,50].…”

“…Another potential limitation to the utilization of senolytics is an apparent resistance of some senescent cell subpopulations. For example, while navitoclax has been shown to eliminate approximately 90% of SA-β-gal positive lung and breast tumor cells, there did appear to be residual surviving tumor cells that could reflect a resistant subpopulation [27]. While repetitive exposure to navitoclax (or other senolytics) might prove to eliminate these cells, possible heterogeneity of the senescent phenotype even within a monoclonally derived tumor cell population might confer resistance to senolysis.…”