Abstract P17: Escape From Therapy-Induced Senescence Drives ABCB1-Mediated Drug Resistance And Evades Aneuploidy Surveillance

Abstract Successful anti-cancer therapy relies on tumor cell killing or senescence induction where cells cease proliferating. However, although senescence initially causes tumor suppression, it can also contribute to tumor recurrence via paracrine tumorigenic action of the senescent secretome. Interestingly, recent findings have challenged the permanence of the senescence cell cycle arrest and shown that cancer cells can escape therapy-induced senescence and contribute to the emergence of residual disease, serving as an additional avenue towards cancer relapse. However, the underlying mechanisms that drive senescence escape, as well as the cellular response of escaped cells, remain largely unknown. Here, we unravel the transcriptomic regulatory modules that underlie senescence escape via a time-resolved approach across the senescence-senescence escape continuum. We show that transition to senescence escape is marked by gradual downregulation of P53 targets and inflammatory SASP genes, prior to shifting towards cell cycle re-entry driven by E2F and MYC. Importantly, we find greater abundance of the drug efflux pump encoded by ABCB1 that promotes drug resistance in chemotherapy rechallenged senescence-escaped cells. Further, these rechallenged cells exhibit mild aneuploidy and evaded surveillance. In addition, we observed elevated genomic instability accompanied by increased basal levels of replication stress in senescence-escaped cells. Taken together, our findings demonstrate a mechanism by which senescence-escaped cells are able to catalyse rapid acquisition and adaptation to resistance without repeated dose-escalating exposure of chemotherapy agents. This could help fuel rapid emergence of chemotherapy-resistant clones that overcome senescence to foster drug resistance in patients. Citation Format: Matius Robert, Rekha Jakhar, Laura Gonzalez-Trueba, Karen Carmelina Crasta. Escape From Therapy-Induced Senescence Drives ABCB1-Mediated Drug Resistance And Evades Aneuploidy Surveillance [abstract]. In: Proceedings of Frontiers in Cancer Science 2025; 2025 Nov 5-7; Singapore. Philadelphia (PA): AACR; Cancer Res 2026;86(13_Suppl):Abstract nr P17.