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An Integrated Stress Response Agent that Modulates DR5-Dependent TRAIL Synergy Reduces Patient-Derived Glioma Stem Cell Viability.

ABSTRACT: The high incidence of glioblastoma recurrence necessitates additional therapeutic strategies. Heterogeneous populations of cells, including glioma stem cells (GSC) have been implicated in disease recurrence. GSCs are able to survive irradiation and temozolomide (TMZ) treatment due to upregulation of DNA damage pathways. One potential strategy to target treatment-resistant tumor populations may be via the integrated stress response (ISR). Modulation of the ISR pathway also allows for sensitization of treatment-resistant cells to TRAIL. We generated a novel cell-based death receptor assay to identify potent inducers of ISR-dependent DR5 expression. We used this assay to screen compounds from three commercially available libraries, and identified 1-benzyl-3-cetyl-2-methylimidazolium iodide (NH125) as a potent inducer of DR5 expression. NH125 engages the EIF2α-ATF4-CHOP axis culminating in DR5 expression at low micromolar doses. Expression of CHOP plays a critical role in NH125-mediated TRAIL synergy. Treatment of GSC with NH125 produces a marked reduction in viability when compared with other cell lines. NH125-treated GSC also synergize with lower doses of TRAIL when compared with all other cell lines tested. Transcriptional analysis of NH125-treated GSC uncovers a unique profile that involves activation of ISR and GADD45 pathways. Treatment of GSC xenografts with encapsulated PEG-PCL-NH125 leads to a sustained decrease in tumor volume. IMPLICATIONS: Taken together, these data suggest that engaging the ISR pathway represents a promising strategy to target treatment refractory GSC that have been implicated in glioblastoma recurrence.

SUBMITTER: Sheikh S

PROVIDER: S-EPMC8797269 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The H3K27M oncohistone mutation, identified in approximately 80% of diffuse intrinsic pontine gliomas (DIPG), is a potential target for therapy. Imipridone ONC201/TIC10 (TRAIL-Inducing Compound #10) induces apoptosis of cancer cells, and has clinical efficacy against H3K27M-mutant DIPG. We demonstrate synergy between ONC201, ONC206 and ONC212, and targeted therapies with known preclinical activity against DIPG. We hypothesized that imipridone combinations with HDAC or proteasome inhibitors may be superior to single agent ONC201 treatment in H3K27M mutant DIPG. Six patient-derived DIPG cell lines (SU-DIPG-IV, SU-DIPG-13, SU-DIPG-25, SU-DIPG-27, SU-DIPG-29, SU-DIPG-36) were exposed to imipridones alone or combinations with histone de-acetylase inhibitors [HDACi], marizomib, etoposide, and temozolomide. Dose-dependent response to imipridones was observed in DIPG cells with half-maximal inhibitory concentration (IC50) of 1.46 µM, 0.11 µM, and 0.03 µM, for ONC201, ONC206, and ONC212, respectively. Upon treatment with the imipridones, DIPG cell lines engaged CLpP/CLPX, the integrated stress response with ATF4 activation, and TRAIL death receptor 5 (DR5) induction. Strong synergy was identified between ONC201 and HDACi panobinostat (combination index [CI] 0.01), romidepsin (CI 0.08) and proteasome inhibitor marizomib (CI 0.19). Synergy was demonstrated between ONC201 and etoposide (CI 0.54), although to a lesser degree than with panobinostat, romidepsin, and marizomib. ONC206 and ONC212 showed similar synergistic effects with panobinostat, romidepsin, and marizomib. Induction of apoptosis was demonstrated with imipridones and panobinostat or romidepsin combinations. Our results suggest increased sensitivity of H3K27M-mutant DIPG cell lines to second generation imipridone therapies, as compared to ONC201. Additionally, there is synergistic cell death with combination of imipridones and panobinostat, romidepsin, or marizomib, which may be further tested in vivo and in clinical trials.

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An Integrated Stress Response Agent that Modulates DR5-Dependent TRAIL Synergy Reduces Patient-Derived Glioma Stem Cell Viability.

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