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Targeting Transcriptional Addiction in MYCN-amplified Neuroblastoma via Super Elongation Complex Disruption

ABSTRACT: MYCN amplification in neuroblastoma predicts particular poor prognosis and directly targeting of MYCN remains a major challenge. We conducted a targeted screen of transcription elongation factors and identified the super elongation complex (SEC) as a unique vulnerability in MYCN-amplified neuroblastoma. Mechanistically, MYCN directly interacts with the SEC subunit EAF1 and recruits the complex to the target gene loci for ensuing processive transcription elongation, rendering MYCN-mediated transcriptional activation highly dependent on SEC. Pharmacological inhibition of SEC by KL-1 or KL-2 elicits selective cell death in MYCN-overexpressing neuroblastoma cells. Furthermore, drug combination screening identifies the BCL-2 inhibitor ABT-199 synergistic with KL-2. Pre-clinical studies manifest that KL-2 and ABT-199 co-treatment significantly suppresses tumorigenesis and shows therapeutic value in multiple neuroblastoma allograft and xenograft models. These findings highlight SEC as a targetable vulnerability, and simultaneous inhibition of SEC and BCL-2 holds great promise for the treatment of MYCN-driven neuroblastoma.

ORGANISM(S): Homo sapiens

PROVIDER: GSE199086 | GEO | 2023/02/27

REPOSITORIES: GEO

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The Super Elongation Complex Drives Transcriptional Addiction in MYCN-amplified Neuroblastoma

Project description:MYCN amplification in neuroblastoma leads to aberrant expression of MYCN oncoprotein, which binds active genes promoting transcriptional amplification. Yet how MYCN coordinates transcription elongation to meet productive transcriptional amplification and which elongation machinery represents MYCN-driven vulnerability remain to be identified. We conducted a targeted screen of transcription elongation factors and identified the super elongation complex (SEC) as a unique vulnerability in MYCN-amplified neuroblastomas. MYCN directly binds EAF1 and recruits SEC to enhance processive transcription elongation. Depletion of EAF1 or AFF1/AFF4, another core subunit of SEC, leads to a global reduction in transcription elongation and elicits selective apoptosis of MYCN-amplified neuroblastoma cells. A combination screen reveals SEC inhibition synergistically potentiates the therapeutic efficacies of FDA-approved BCL2 antagonist ABT-199, in part due to suppression of MCL1 expression, both in MYCN-amplified neuroblastoma cells and in patient-derived xenografts. These findings identify disruption of the MYCN-SEC regulatory axis as a promising therapeutic strategy in neuroblastoma.

2023-05-10 | PXD039332 | Pride

Off-target based drug repurposing opportunities for tivantinib in acute myeloid leukemia

Project description:GSK3alpha has been identified as a new target in the treatment of acute myeloid leukemia (AML). However, most GSK3 inhibitors lack specificity for GSK3alpha over GSK3beta and other kinases. We have previously shown in lung cancer cells that GSK3alpha and to a lesser extent GSK3beta are inhibited by the advanced clinical candidate tivantinib (ARQ197), which was designed as a MET inhibitor. Thus, we hypothesized that tivantinib would be an effective therapy for the treatment of AML. Here, we show that tivantinib has potent anticancer activity across several AML cell lines and primary patient cells. Tivantinib strongly induced apoptosis, differentiation and G2/M cell cycle arrest and caused less undesirable stabilization of beta-catenin compared to the pan-GSK3 inhibitor LiCl. Subsequent drug combination studies identified the BCL-2 inhibitor ABT-199 to synergize with tivantinib. Interestingly, the addition of ABT-199 to tivantinib completely abrogated tivantinib induced beta-catenin stabilization. Tivantinib alone, or in combination with ABT-199, downregulated anti-apoptotic MCL-1 and BCL-XL levels, which likely contribute to the observed synergy. Importantly, tivantinib as single agent or in combination with ABT-199 significantly inhibited the colony forming capacity of primary patient AML bone marrow mononuclear cells. In summary, tivantinib is a novel GSK3alpha/beta inhibitor that potently kills AML cells and tivantinib single agent or combination therapy with ABT-199 may represent attractive new therapeutic opportunities for AML.

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Allosteric transcription stimulation by super elongation complex

Project description:The super elongation complex (SEC) contains the positive transcription elongation factor b (P-TEFb) and a subcomplex, ELL2-EAF1, which stimulates transcription elongation by RNA polymerase II (Pol II). Here we report the cryo-EM structure of ELL2-EAF1 bound to a Pol II elongation complex at 2.8 Å resolution. The ELL2-EAF1 dimerization module directly binds the Pol II lobe, explaining how SEC delivers P-TEFb to Pol II. The same site on the lobe also binds the initiation factor TFIIF, consistent with SEC binding only after the transition from transcription initiation to elongation. Structure-guided functional analysis shows that elongation stimulation requires the dimerization module and an ELL2 protein linker that tethers this module to the Pol II protrusion. Our results show that SEC stimulates elongation allosterically and indicate that this stimulation involves stabilization of a further closed conformation of the Pol II active center cleft.

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Targeting Processive Transcription Elongation via SEC Disruption for MYC-Induced Cancer Therapy

Project description:The super elongation complex (SEC) is required for robust and productive transcription through release of RNA polymerase II (Pol II) with its P-TEFb module and promoting transcriptional processivity with its ELL2 subunit. Malfunction of SEC contributes to multiple human diseases including cancer. Here, we identify peptidomimetic lead compounds, KL-1 and its structural homolog KL-2, which disrupt the interaction between the SEC scaffolding protein AFF4 and P-TEFb, resulting in impaired release of Pol II from promoter-proximal pause sites and a reduced average rate of processive transcription elongation. SEC is required for induction of heat-shock genes and treating cells with KL-1 and KL-2 attenuates the heat-shock response from Drosophila to human. SEC inhibition downregulates MYC and MYC-dependent transcriptional programs in mammalian cells and delays tumor progression in a mouse xenograft model of MYC-driven cancer, indicating that small-molecule disruptors of SEC could be used for targeted therapy of MYC-induced cancer.

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Project description:Genome wide DNA methylation profiling of parental, ABT-199 resistant population, and ABT-199 resistant clones from 3 acute myelogenous leukemia (AML) cell lines (MOLM-13, MV-4-11, OCI-AMLO2). The Illumina Infinium MethylationEPIC Human DNA methylation Beadchip was used to obtain DNA methylation profiles across approximately 850,000 CpGs from AML cell line samples. Samples include 4 ABT-199 sensitive parental MOLM-13 population samples, 4 ABT-199 resistant MOLM-13 population samples, 3 ABT-199 resistant MOLM-13 S2 clone samples, 3 ABT-199 resistant MOLM-13 S5 clone samples, 4 ABT-199 resistant MOLM-13 S6 clone samples, 3 ABT-199 sensitive parental MV-4-11 population samples, 3 ABT-199 resistant MV-4-11 population samples, 3 ABT-199 sensitive parental OCI-AML2 population samples, 3 ABT-199 resistant OCI-AML2 population samples, 3 ABT-199 resistant OCI-AML2 S1 clone samples, 3 ABT-199 resistant OCI-AML2 S2 clone samples, 3 ABT-199 resistant OCI-AML2 S8 clone samples.

2022-01-12 | GSE193254 | GEO

Chromosomal deletion and chromatin remodeling Drive ABT-199 Resistance in B-cell Lymphomas [RNA-seq]

Project description:Drug-tolerant “persister” cells underlie the emergence of drug-resistant clones and allow residual tumors to survive therapy; thus, represent an attractive therapeutic target to mitigate relapse. With the promising outcome, yet some resistance cases surfaced after the approval of venetoclax (ABT-199), we defined a novel invasive drug resistance mechanism induced by Bcl2 inhibitor via examining the evolution of drug tolerant persister clones generated with ABT-199 treatment. The ABT-199 drug-tolerant persister cells showed genetic alteration by losing the copy number at 18q21 paralleled with BCL2, PMAIP1 and TCF4 gene downregulation. The persister status are generated through major enhancer-remodeling mediated transcriptional activation of the super enhancer, which offered unique opportunity for overcoming the drug resistance. The insight of major determinant for ABT-199 persistence evolution identified the molecular vulnerability in Bcl2 inhibitor resistant lymphoma cells through CDK7 pathway inhibition. The combined CDK7 and BCL2 inhibition was found to be more effective against ABT-199 persistence ex vivo and in vivo rather than the parental line, and CDK7 inhibition eliminated the persister phenotype by blocking dynamic active enhancer formation to further prevent the evolution of drug resistance. Together, these studies unified genetic alteration and non-mutational adaptive response as a drug resistance mechanism, more importantly, demonstrated a rationale for transcriptional inhibition-based combination strategies to prevent and overcome drug resistance in B-cell malignancies.

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Chromosomal deletion and chromatin remodeling Drive ABT-199 Resistance in B-cell Lymphomas [ChIP-seq]

2019-05-01 | GSE116097 | GEO

Gene expression data of parental and ibrutinib-resistant TMD8 cells.

Project description:Diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) are the most prevalent B-lymphocyte neoplasms in which abnormal activation of the Bruton’s tyrosine kinase (BTK)–mediated B-cell receptor (BCR) signaling pathway contributes to pathogenesis. Ibrutinib is an oral covalent BTK inhibitor that has shown some efficacy in both indications. To improve ibrutinib efficacy through combination therapy, we first investigated differential gene expression in parental and ibrutinib-resistant cell lines to better understand the mechanisms of resistance. Ibrutinib-resistant TMD8 cells had higher BCL2 gene expression and increased sensitivity to ABT-199, a BCL-2 inhibitor. Consistently, clinical samples from ABC-DLBCL patients who experienced poorer response to ibrutinib had higher BCL2 gene expression. We further demonstrated synergistic growth suppression by ibrutinib and ABT-199 in multiple ABC-DLBCL, GCB-DLBCL, and FL lymphoma cell lines. The combination of both drugs also reduced colony formation, increased apoptosis, and inhibited tumor growth in a TMD8 xenograft model. A synergistic combination effect was also found in ibrutinib-resistant cells generated by either genetic mutation or drug treatment. Together, these findings suggest a potential clinical benefit from ibrutinib and ABT-199 combination therapy.

2017-04-30 | GSE93985 | GEO

Expression data from DLBCL tumor biopsies

2017-04-30 | GSE93984 | GEO

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