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• W2885202252 abstract "Abstract Introduction: Tuberous sclerosis complex (TSC) is characterized by tumor development in the brain, heart, skin, kidney and lungs. While everolimus is approved for treatment of TSC angiomyolipoma and TSC subependymal giant cell astrocytoma, responses are not complete and tumor regrowth occurs after treatment cessation. Therapies for TSC that induce a selective cytocidal response in TSC-null cells are not currently available, and are highly desirable for TSC patients. In TSC tumors loss of the TSC1/TSC2 protein complex leads to activation of mTORC1 with downstream effects on anabolism and cell growth. We hypothesized that mTORC1 activation would also enhance mRNA transcription and that this effect might create a therapeutic vulnerability. In addition, we hypothesized that rapamcyin treatment of TSC-null cells would lead to complex compensatory effects on transcription, and that synergy might be seen in co-treatment with a transcriptional inhibitor. Cyclin-dependent kinase 7 (CDK7) plays a critical role in phosphorylation of RNA polymerase II, thus regulating RNA transcription. Recent screens have identified THZ1, a selective and covalent CDK7 inhibitor, as a cytocidal compound for several cancer types. We hypothesized that THZ1 and inhibitors of CDK7 might be selectively lethal to TSC-null cells in TSC-associated tumors. Methods: Drug sensitivity assay was performed using Quant-it PicoGreen. FACS and assays of apoptosis, such as Propidium Iodide/Annexin V staining and immunoblot for cleaved caspase 3 were used to assess apoptosis. We used RNA-sequencing and metabolome profiling to assess metabolomics and transcriptional effects of THZ1, and investigate the novel hypothesis that targeting transcription triggers selective cell death in TSC-null cells. To further assess the therapeutic potential of THZ1+/-Rapamycin in TSC, In vivo treatment studies were performed using xenografts in athymic nude mice. Results: Drug sensitivity assays to THZ1+/- Rapamycin revealed selective lethality for both the TSC1-null HCV29 bladder cancer derived cell line vs. addback TSC1-HCV29 and the TSC2-null 621-101 angiomyolipoma cell line vs. TSC2 addback 621-103. The IC50 of each of TSC1/TSC2 null cells was 6-10 fold lower vs. addback lines. FACS assay of apoptosis showed 37% of HCV29 cells Annexin V+ in comparison to 3% of TSC1-HCV29 cells. IB showed cleaved Caspase 3 only in THZ1-treated TSC1-null cells. RNA-seq on samples treated with THZ1(30nm) for 6 hours identified many genes with markedly different expression: e.g. 1128 genes showed a &gt; 5-fold lower expression in THZ1-treated HCV29 compared with THZ1-treated TSC1-HCV29 cells. Genes involved in glutathione biosynthesis pathway such as GCLC (glutamate-cysteine ligase catalytic subunit) showed an 82% reduction in mRNA levels in THZ1-treated HCV29 cells vs. TSC1-HCV 29. Metabolite analyzes confirmed that THZ1 caused a marked decrease (4 fold) in glutathione levels, and supplemental GSH-MEE rescued cell death induction in response to THZ1.THZ1(10mg/kg/twice daily) +/- Rapamycin (3mg/kg/3 days week) for 30 days markedly reduced the tumor growth rate in the in vivo TSC1-null xenograft model and prevented tumor regrowth compared to either Rapamycin or vehicle. Conclusions: These findings reveal that targeting transcriptional addiction will selectively induce cell death of TSC-null cells. We hypothesize that targeting transcription with a covalent CDK7 inhibitor has novel therapeutic benefit for patients with TSC. Citation Format: Mahsa zarei, Heng Du, Rachel E. Yan, Yubao Wang, Thingu Zhang, John M. Asara, David J. Kwiatkowski. Targeting transcriptional addiction for the treatment of TSC [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr LB-B24." @default.
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• W2885202252 date "2018-01-01" @default.
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• W2885202252 title "Abstract LB-B24: Targeting transcriptional addiction for the treatment of TSC" @default.
• W2885202252 doi "https://doi.org/10.1158/1535-7163.targ-17-lb-b24" @default.
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