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A Rapid Screening Workflow to Identify Potential Combination Therapy for GBM using Patient-Derived Glioma Stem Cells
Published on: March 28, 2021
Super-enhancer inhibitors THZ2 and JQ1 reverse temozolomide resistance in glioblastoma by suppressing SE-driven SOX9
Xinqi Teng1,2,3, Yiming Wang1,3, Qiang Qu4,5,3
1Department of Pharmacy, the Second Xiangya Hospital, Central South University; Institute of Clinical Pharmacy, Central South University, Changsha 410011, Hunan, China.
Abstract:
Aim: Glioblastoma (GBM) is the most malignant grade of glioma, characterized by high recurrence, poor prognosis, and frequent chemoresistance. There is an urgent need for alternative treatment strategies. In this study, we evaluated the effects of THZ2, a covalent inhibitor targeting the super-enhancer (SE) component CDK7, on GBM growth and chemoresistance. We also used another SE inhibitor, JQ1, to further validate the inhibitory effects of targeting SEs in GBM, thereby providing new treatment strategies for patients. Methods: A variety of in vitro and in vivo assays were performed to explore the anti-GBM effects of SE inhibitors. We assessed the effects of SE inhibitors in combination with temozolomide (TMZ) on GBM cells and calculated the combination index. Additionally, CUT&RUN assays were conducted to examine protein-DNA interactions. Results: THZ2 inhibited the proliferation, migration, and invasion of GBM cells and induced cell cycle arrest and apoptosis. Furthermore, both THZ2 and JQ1 exhibited synergistic antitumor effects when combined with TMZ in GBM cells. Notably, THZ2 reversed TMZ resistance in GBM cells by suppressing the expression of the SE-associated gene SOX9. We also found that SOX9, CDK7, and BRD4 interact with histone H3K27ac. Conclusion: Our findings demonstrate that SE inhibitors exert antitumor effects in GBM and act synergistically with TMZ. THZ2 may enhance chemosensitivity by downregulating the SE-related gene SOX9, and it holds promise as a novel therapeutic agent for GBM patients.
Insights
Super-enhancer inhibitors like THZ2 show promise for treating glioblastoma (GBM). These inhibitors, targeting CDK7, combat GBM growth and overcome chemoresistance, offering new therapeutic strategies for patients.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Glioblastoma (GBM) is an aggressive brain tumor with high recurrence and poor outcomes.
- Current treatments often face chemoresistance, necessitating novel therapeutic approaches.
Purpose of the Study:
- To evaluate the efficacy of THZ2, a CDK7 inhibitor targeting super-enhancers (SEs), against GBM growth and chemoresistance.
- To validate SE inhibition's anti-GBM effects using JQ1 and explore combination therapies with temozolomide (TMZ).
Main Methods:
- In vitro and in vivo assays were used to assess SE inhibitors' anti-GBM effects.
- Combination studies with temozolomide (TMZ) and combination index calculations were performed.
- CUT&RUN assays investigated protein-DNA interactions.
Main Results:
- THZ2 inhibited GBM cell proliferation, migration, invasion, and induced apoptosis and cell cycle arrest.
- THZ2 and JQ1 demonstrated synergistic antitumor effects with TMZ in GBM cells.
- THZ2 reversed TMZ resistance by downregulating SOX9, an SE-associated gene; SOX9, CDK7, and BRD4 interact with histone H3K27ac.
Conclusions:
- Super-enhancer inhibitors exhibit antitumor activity in GBM and synergize with TMZ.
- THZ2 shows potential as a novel GBM therapeutic by enhancing chemosensitivity via SOX9 downregulation.
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