Abstract PR013: BH3 profiling of senescent cancer cells to identify mechanisms of resistance to ABT-263

Abstract

Abstract Senescent cells rely on anti-apoptotic signaling for their survival, which can be targeted by senolytic agents. ABT-263 is a broad acting senolytic that targets anti-apoptotic proteins BCL-2, BCL-xL and BCL-W. Our group has shown that ABT-263 has a senolytic effect in most cancer cell lines, but not in all. This raised the question why certain senescent cancer cells undergo into apoptosis after treatment with ABT-263, while others remain refractory. To investigate this, we performed BH3 profiling, a technique that measures apoptotic priming (readiness to undergo into apoptosis) and apoptotic dependencies. We found that BH3 profiling in senescent cells requires specific optimization, and it determines that senescent ABT-263 sensitive cells highly depend on specific anti-apoptotic signaling, while ABT-263 resistant cells did not. Moreover, we found that ABT-263 sensitive cells were more primed to apoptosis compared to resistant cells. Intriguingly, this correlation was already apparent in the parental state. Nevertheless, we found that senescent cells were less primed to apoptosis than their parental counterparts, which was in contrast to what we expected. In conclusion, whether senescent cells will respond to ABT-263 is already determined in the parental state, and they become dependent on anti-apoptotic signaling for their survival. The observation that senescent cells were less primed to apoptosis was surprising, and we intend to further understand how it is possible that senescent cells are less primed to apoptosis, but still sensitive to ABT-263. Citation Format: Fleur Jochems, Julie A. MacDonald, Chrysiida Baltira, Veerle Daniels, Mark de Gooijer, Olaf Van Tellingen, Anthony Letai, René Bernards. BH3 profiling of senescent cancer cells to identify mechanisms of resistance to ABT-263 [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr PR013.