Glioma Stem Cells Are Sensitized to BCL-2 Family Inhibition by Compromising Histone Deacetylases

Merati, Aran; Kotian, Spandana; Acton, Alexus; Placzek, William; Smithberger, Erin; Shelton, Abigail K.; Miller, C. Ryan; Stern, Josh L.

doi:10.3390/ijms241813688

Cited by 2 publications

References 81 publications

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Cell death in glioblastoma and the central nervous system

Malone,

LaCasse,

Beug

2024

Cell Oncol.

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Glioblastoma is the commonest and deadliest primary brain tumor. Glioblastoma is characterized by significant intra- and inter-tumoral heterogeneity, resistance to treatment and dismal prognoses despite decades of research in understanding its biological underpinnings. Encompassed within this heterogeneity and therapy resistance are severely dysregulated programmed cell death pathways. Glioblastomas recapitulate many neurodevelopmental and neural injury responses; in addition, glioblastoma cells are composed of multiple different transformed versions of CNS cell types. To obtain a greater understanding of the features underlying cell death regulation in glioblastoma, it is important to understand the control of cell death within the healthy CNS during homeostatic and neurodegenerative conditions. Herein, we review apoptotic control within neural stem cells, astrocytes, oligodendrocytes and neurons and compare them to glioblastoma apoptotic control. Specific focus is paid to the Inhibitor of Apoptosis proteins, which play key roles in neuroinflammation, CNS cell survival and gliomagenesis. This review will help in understanding glioblastoma as a transformed version of a heterogeneous organ composed of multiple varied cell types performing different functions and possessing different means of apoptotic control. Further, this review will help in developing more glioblastoma-specific treatment approaches and will better inform treatments looking at more direct brain delivery of therapeutic agents.

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Cell death in glioblastoma and the central nervous system

Malone,

LaCasse,

Beug

2024

Cell Oncol.

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SNAI2 cooperates with MEK1/2 and HDACs to suppress BIM- and BMF-dependent apoptosis inTERTpromoter mutant cancers

Tandon,

Stern

2024

Preprint

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Cancers with TERT promoter mutations (TPM) display elevated RAS pathway signaling and mesenchymal traits, and associate with lower patient survival rates. We examined whether RAS pathway signaling in TPM cancers cooperates with mesenchymal features to drive resistance to apoptosis. We observed that RAS pathway signaling in TPM cancers inhibited apoptosis by downregulating the pro-apoptotic protein BIM. By using inhibitors of MEK1/2 kinases, we rescued the ability of TPM cancer cells to undergo apoptosis, which may have implications for targeted therapies. To further capitalize on this rescue, we explored combination treatments to drive apoptotic cell death. Treatment with the pan-BCL2 inhibitor, navitoclax (NX), in combination with MEK inhibition, significantly increased apoptosis, indicating that these cells are capable of undergoing intrinsic apoptosis, with BIM likely playing a critical role. Further, we found that transcriptional reprogramming of the mesenchymal state of TPM cancers using histone deacetylase inhibitors (HDACi) resulted in a synergistic increase in apoptosis, contingent upon BIM de-repression. Notably, the cause of this apoptosis appeared to be independent of DNA damage. The suppression of the mesenchymal transcription factor SNAI2, which has known roles in recruiting HDACs to silence gene expression, amplified apoptosis. Mechanistically, knockdown of SNAI2 impaired the cellular DNA repair leading to elevated basal levels of phosphorylated H2AX. Our findings show that TPM cancers exhibit specific small molecule vulnerabilities, driven by the convergence of RAS-MEK signaling and impaired HDAC regulation dependent on pro-apoptotic BH3-only proteins. Based on our findings, we propose that stratifying cancers based on TPM may identify a subset of tumors that are responsive to innovative combinations of inhibitors targeting these axes.

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Glioma Stem Cells Are Sensitized to BCL-2 Family Inhibition by Compromising Histone Deacetylases

Cited by 2 publications

References 81 publications

Cell death in glioblastoma and the central nervous system

Cell death in glioblastoma and the central nervous system

SNAI2 cooperates with MEK1/2 and HDACs to suppress BIM- and BMF-dependent apoptosis inTERTpromoter mutant cancers

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