Selective Vulnerability of Senescent Glioblastoma Cells to BCL-XL Inhibition

Masum Rahman, Ian Olson, Moustafa Mansour, Lucas P. Carlstrom, Rujapope Sutiwisesak, Rehan Saber, Karishma Rajani, Arthur E. Warrington, Adam Howard, Mark Schroeder, Sisi Chen, Paul A. Decker, Eliot F. Sananikone, Yi Zhu, Tamar Tchkonia, Ian F. Parney, Sandeep Burma, Desmond Brown, Moses Rodriguez, Jann N. Sarkaria, James L. Kirkland, Terry C. Burns

Glioblastoma is a rapidly fatal malignancy typically treated with radiation and Temozolomide (TMZ), an alkylating chemotherapeutic. These cytotoxic therapies cause oxidative stress and DNA damage, yielding a senescent-like state of replicative arrest in surviving tumor cells. Unfortunately, recurrence is inevitable, and may be driven by surviving tumor cells eventually escaping senescence. A growing number of socalled "senolytic" drugs have been recently identified that are defined by their ability to selectively eliminate senescent cells. A growing inventory of senolytic drugs are under consideration for several diseases associated with aging, inflammation, DNA damage, as well as cancer. Ablation of senescent tumor cells after radiation and chemotherapy could help mitigate recurrence by decreasing the burden of residual tumor cells at risk of recurrence. This strategy has not been previously explored for glioblastoma. We evaluated a panel of 10 previously described senolytic drugs to determine if any could exhibit selective activity against human glioblastoma persisting after exposure to radiation or TMZ. Three of the 10 drugs have known activity against BCL-XL and preferentially induced apoptosis in radiated or TMZtreated glioma. This senolytic activity was observed in 12/12 human GBM cell lines. Efficacy could not be replicated with BCL-2 inhibition or senolytic agents acting against other putative senolytic targets. Knockdown of BCL-XL decreased survival of radiated GBM cells, whereas knockdown of BCL-2 or BCL-W yielded no senolytic effect. Implications: These findings imply that molecularly heterogeneous GBM lines share selective senescence-induced Bcl-XL dependency increase the significance and translational relevance of the senolytic therapy for latent glioma.