Targeting cIAP2 in a novel senolytic strategy prevents glioblastoma recurrence after radiotherapy.

in EMBO molecular medicine by Nozomi Tomimatsu, Luis Fernando Macedo Di Cristofaro, Suman Kanji, Lorena Samentar, Benjamin Russell Jordan, Ralf Kittler, Amyn A Habib, Jair Machado Espindola-Netto, Tamara Tchkonia, James L Kirkland, Terry C Burns, Jann N Sarkaria, Andrea Gilbert, John R Floyd, Robert Hromas, Weixing Zhao, Daohong Zhou, Patrick Sung, Bipasha Mukherjee, Sandeep Burma

TLDR

  • Irradiation-induced senescence in glioblastoma tumors promotes tumor recurrence by stimulating the production of pro-inflammatory cytokines, which in turn activate surrounding tumor cells and facilitate the emergence of recurrent tumors.

Abstract

Glioblastomas (GBM) are routinely treated with high doses of ionizing radiation (IR), yet these tumors recur quickly, and the recurrent tumors are highly therapy resistant. Here, we report that IR-induced senescence of tumor cells counterintuitively spurs GBM recurrence, driven by the senescence-associated secretory phenotype (SASP). We find that irradiated GBM cell lines and patient derived xenograft (PDX) cultures senesce rapidly in a p21-dependent manner. Senescent glioma cells upregulate SASP genes and secrete a panoply of SASP factors, prominently interleukin IL-6, an activator of the JAK-STAT3 pathway. These SASP factors collectively activate the JAK-STAT3 and NF-κB pathways in non-senescent GBM cells, thereby promoting tumor cell proliferation and SASP spreading. Transcriptomic analyses of irradiated GBM cells and the TCGA database reveal that the cellular inhibitor of apoptosis protein 2 (cIAP2), encoded by the BIRC3 gene, is a potential survival factor for senescent glioma cells. Senescent GBM cells not only upregulate BIRC3 but also induce BIRC3 expression and promote radioresistance in non-senescent tumor cells. We find that second mitochondria-derived activator of caspases (SMAC) mimetics targeting cIAP2 act as novel senolytics that trigger apoptosis of senescent GBM cells with minimal toxicity towards normal brain cells. Finally, using both PDX and immunocompetent mouse models of GBM, we show that the SMAC mimetic birinapant, administered as an adjuvant after radiotherapy, can eliminate senescent GBM cells and prevent the emergence of recurrent tumors. Taken together, our results clearly indicate that significant improvement in GBM patient survival may become possible in the clinic by eliminating senescent cells arising after radiotherapy.

Overview

  • The study investigates the role of ionizing radiation-induced senescence in glioblastoma (GBM) tumors, challenging the conventional wisdom that senescence is a tumor-suppressing mechanism.
  • The researchers used a combination of cell cultures, patient-derived xenografts, and a mouse model to demonstrate that senescent GBM cells promote tumor recurrence by secreting a senescence-associated secretory phenotype (SASP) and activating the JAK-STAT3 and NF-κB pathways in surrounding tumor cells.
  • The study identifies the cellular inhibitor of apoptosis protein 2 (cIAP2) as a key survival factor for senescent glioma cells and shows that targeting cIAP2 with SMAC mimetics can eliminate senescent tumor cells and prevent recurrent tumors.

Comparative Analysis & Findings

  • The study reveals that irradiated GBM cell lines and patient-derived xenografts senesce rapidly in a p21-dependent manner, leading to the upregulation of SASP genes and the secretion of SASP factors.
  • Transcriptomic analyses demonstrate that the cIAP2 gene is a potential survival factor for senescent glioma cells, and that SMAC mimetics can target and eliminate these cells.
  • The study shows that the SMAC mimetic birinapant can eliminate senescent GBM cells and prevent recurrent tumors in both patient-derived xenograft and immunocompetent mouse models.

Implications and Future Directions

  • The study's findings suggest that targeting senescent cells with SMAC mimetics may be a promising new approach to improving GBM patient survival and preventing recurrent tumors.
  • Future studies should investigate the potential benefits of combining SMAC mimetics with standard-of-care therapies in clinical trials.
  • Elucidating the specific mechanisms by which senescent GBM cells promote tumor recurrence and identifying additional therapeutic targets may help to refine the development of senolytic therapies for GBM.
Read Full Article