Selective Vulnerability of Senescent Glioblastoma Cells to BCL-XL Inhibition

Abstract

Glioblastoma (GBM) 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 so-called “senolytic” drugs have been recently identified that are defined by their ability to selectively eliminate senescent cells. A growing inventory of senolytic drugs is 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 GBM. We evaluated a panel of 10 previously described senolytic drugs to determine whether any could exhibit selective activity against human GBM 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 TMZ-treated glioma. This senolytic activity was observed in 12 of 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.

EA.hy926 Cells and HUVECs Share Similar Senescence Phenotypes but Respond Differently to the Senolytic Drug ABT-263

“…Only ABT-263 selectively induced the apoptosis of DOX-induced senescent HUVECs, but not EA.hy926 cells. The demonstrated effectiveness of different senolytics was in agreement with a recent study evaluating the sensitivity of radiation-induced senescent glioblastoma cells to different senolytics [46]. Similar to our findings in HUVECs, only the inhibition of BCL-xL, but not BCL-2 nor other senolytic targets, was able to demonstrate senolytic activity.…”

Cellular senescence in malignant cells promotes tumor progression in mouse and patient Glioblastoma

“…Despite encouraging results in mouse GBM models, clinical studies show major side effects of ABT263 such as thrombocytopenia and neutropenia caused by BCL-xL inhibition 80 , limiting the use of BCL-xL inhibitors as safe and effective anticancer agents. The selective BCL2 inhibitor ABT199 (Venetoclax) which spares the platelets, displays variable results on senescent glioma cells, in vitro 81 , 82 . Administration of a combination of dasatinib and quercitin, a multi-tyrosine kinase inhibitor and a natural flavonoid respectively, eliminates efficiently senescent cells in different pathologies in the mouse including neurodegenerative diseases 83 , 84 .…”

“…GBMs which are characterized by intra-tumoral heterogeneity, are thus not the ideal candidate for the use of this strategy. Nonetheless, radiation and TMZ chemotherapy induce senescence in glioma cells in vitro and sensitize these cells to anti-apoptotic inhibitors with distinct efficacy according to the patient-derived cell lines, suggesting that this strategy may be relevant for some patients with GBM 82 , 88 . Based on our work which focused on naturally-occurring senescence, we hypothesize that senolytics combined with conventional treatment could have a double action by depleting both resident and therapy-induced senescent cells which may potentialize their effect.…”

Bcl-2 family inhibitors sensitize human cancer models to target therapy

“…As the mechanism at the basis of the potentiating effect of BH3 mimetics on target therapy observed in ovarian cancer and melanoma, we cannot exclude a possible senolytic effect reported by some Bcl-2 family inhibitors [64,65]. We can speculate these inhibitors may potentiate the effect of PARPi and MAPKi through the selective activation of apoptosis in olaparib-and dabrafenib/trametinib-induced senescent cells [66-68], as some preclinical evidences suggest [65,[69][70][71][72][73].…”