CDK7 controls E2F- and MYC-driven proliferative and metabolic vulnerabilities in multiple myeloma
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA723315 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14287521.fastq.gz | Fastqsanger.gz | |||
| SRR14287522.fastq.gz | Fastqsanger.gz | |||
| SRR14287523.fastq.gz | Fastqsanger.gz | |||
| SRR14287524.fastq.gz | Fastqsanger.gz | |||
| SRR14287525.fastq.gz | Fastqsanger.gz |
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Project description:Therapeutic targeting of CDK7 has proven beneficial in pre-clinical studies, yet the off-target effects of currently available CDK7 inhibitors make it difficult to pinpoint the exact mechanisms behind MM cell death mediated by CDK7 inhibition. Here, we show that CDK7 expression positively correlates with E2F and MYC transcriptional programs in multiple myeloma (MM) patient cells; and its selective targeting counteracts E2F activity via perturbation of the CDKs/Rb axis and impairs MYC-regulated metabolic gene signatures translating into defects in glycolysis and reduced levels of lactate production in MM cells. CDK7 inhibition using the covalent small molecule inhibitor YKL-5-124 elicits a strong therapeutic response with minimal effects on normal cells, and causes in vivo tumor regression increasing survival in several MM mouse models including a genetically engineered mouse model of MYC-dependent MM. Through its role as a critical cofactor and regulator of MYC and E2F activity, CDK7 is therefore a master regulator of oncogenic cellular programs supporting MM growth and survival, and a valuable therapeutic target providing rationale for development of YKL-5-124 for clinical use.
2023-02-01 | GSE172441 | GEO
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Project description:Cyclin dependent kinases (CDKs) are high value therapeutical targets owing to their important roles in regulating transcription and the cell cycle — two pathways commonly altered in cancer and especially in multiple myeloma (MM). Among CDKs, CDK7 uniquely bridges cell cycle and transcriptional control by activating other cell cycle CDKs and forming the general transcription factor TFIIH. Utilizing a recently developed highly selective covalent inhibitor of CDK7, we demonstrate that CDK7 inhibition elicits a strong therapeutic response in MM blocking proliferation in vitro and driving tumor regression and prolonged survival in vivo. CDK7 inhibition counteracts molecular hallmarks of deregulated cell cycle control at the G1/S checkpoint. Additionally, we show CDK7 inhibition selectively downregulates oncogenic E2F and cell cycle gene expression programs. Combination treatment with JQ1 which target oncogenic enhancer driven gene expression programs proved highly synergistic. These results support CDK7 as an attractive and therapeutically actionable molecular vulnerability in MM. Cell count normalized RNA-seq in Sensitive MM cell lines (H929 and MM1S; 24 total samples; 3 technical replicates) upon treatment with the selective covalent CDK7 inhibitor YKL-5-124 Mariateresa,Fulciniti Nikhil,Munshi
2022-04-01 | GSE172444 | GEO
Project description:Cyclin dependent kinases (CDKs) are high value therapeutical targets owing to their important roles in regulating transcription and the cell cycle — two pathways commonly altered in cancer and especially in multiple myeloma (MM). Among CDKs, CDK7 uniquely bridges cell cycle and transcriptional control by activating other cell cycle CDKs and forming the general transcription factor TFIIH. Utilizing a recently developed highly selective covalent inhibitor of CDK7, we demonstrate that CDK7 inhibition elicits a strong therapeutic response in MM blocking proliferation in vitro and driving tumor regression and prolonged survival in vivo. CDK7 inhibition counteracts molecular hallmarks of deregulated cell cycle control at the G1/S checkpoint. Additionally, we show CDK7 inhibition selectively downregulates oncogenic E2F and cell cycle gene expression programs. Combination treatment with JQ1 which target oncogenic enhancer driven gene expression programs proved highly synergistic. These results support CDK7 as an attractive and therapeutically actionable molecular vulnerability in MM. Cell count normalized RNA-seq in Resistant MM cell lines (XG1 and AMO1; 18 total samples; 3 technical replicates) upon treatment with the selective covalent CDK7 inhibitor YKL-5-124 Mariateresa,Fulciniti Nikhil,Munshi
2022-04-01 | GSE172443 | GEO
Project description:Cyclin dependent kinases (CDKs) are high value therapeutical targets owing to their important roles in regulating transcription and the cell cycle — two pathways commonly altered in cancer and especially in multiple myeloma (MM). Among CDKs, CDK7 uniquely bridges cell cycle and transcriptional control by activating other cell cycle CDKs and forming the general transcription factor TFIIH. Utilizing a recently developed highly selective covalent inhibitor of CDK7, we demonstrate that CDK7 inhibition elicits a strong therapeutic response in MM blocking proliferation in vitro and driving tumor regression and prolonged survival in vivo. CDK7 inhibition counteracts molecular hallmarks of deregulated cell cycle control at the G1/S checkpoint. Additionally, we show CDK7 inhibition selectively downregulates oncogenic E2F and cell cycle gene expression programs. Combination treatment with JQ1 which target oncogenic enhancer driven gene expression programs proved highly synergistic. These results support CDK7 as an attractive and therapeutically actionable molecular vulnerability in MM. Cell count normalized RNA-seq in Resistant MM cell lines (XG1 and AMO1; 18 total samples; 3 technical replicates) upon treatment with the selective covalent CDK7 inhibitor YKL-5-124 Mariateresa,Fulciniti Nikhil,Munshi
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Project description:Cyclin-dependent kinase 7 (CDK7) functions as both a cell cycle regulator through activation of CDKs 1, 2, 4, and 6, and as a critical component of transcription factor II H (TFIIH) mediating RNA Polymerase II transcription. This study investigates the transcriptional impact of Q901, a highly selective CDK7 inhibitor in clinical development. Our findings demonstrate that Q901 primarily disrupts oncogenic transcription programs driven by MYC and E2F, evidenced by dramatic stabilization of CDK7 binding and reduced occupancy of MYC, E2F, and RNA Pol II at promoter-proximal regions. This leads to downregulation of genes involved in DNA damage repair and cell cycle control pathways. Further investigation revealed a novel therapeutic mechanism to overcome topoisomerase I (TOP1) inhibitor resistance. While cancer cells typically evade TOP1 inhibitors when elongating RNA Pol II encounters TOP1-DNA protein crosslinks (TOP1-DPCs), triggering repair mechanisms, Q901 prevents RNA Pol II transition from initiation to elongation as well as DNA repair pathway, thereby stabilizing TOP1-DPCs. In vivo studies demonstrated synergistic tumor growth inhibition when combining Q901 with TOP1 inhibitor-based antibody-drug conjugates (TOP1i-ADCs), including trastuzumab deruxtecan and sacituzumab govitecan. These results collectively demonstrate that a combination of Q901 and TOP1i-ADC could be a promising therapeutic approach for cancers with limited response to TOP1i-ADC therapy.
2026-02-12 | GSE292860 | GEO
Project description:Immunotherapies targeting surface antigens have transformed the treatment landscape of multiple myeloma (MM), with GPRC5D emerging as a promising therapeutic target, although its physiological function remains undefined. Mono-allelic loss of GPRC5D is frequently observed in newly diagnosed MM patients, and the incidence of acquired GPRC5D alterations increases following exposure to GPRC5D-directed therapies. However, the functional consequences of both baseline mono-allelic and therapy-induced biallelic GPRC5D alterations remain poorly understood. In this study, we modeled various GPRC5D genetic alterations to investigate their impact on myeloma cell biology and responsiveness to GPRC5D-targeted immunotherapies. Our results demonstrate that mono-allelic GPRC5D loss reduces surface expression of the antigen and confers resistance to GPRC5D-directed therapies. Complete loss of GPRC5D induces transcriptional and phosphoproteomic reprogramming that promotes a proliferative phenotype and alters chemokine signaling. Clonal competition assays reveal that both functional and non-functional CAR-T cells preferentially select for GPRC5D-deficient cells. Collectively, our findings reveal that GPRC5D loss exerts a dual effect in MM by driving resistance to GPRC5D-targeted immunotherapies and enhancing tumor fitness through proliferative reprogramming.
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Project description:The relationship between promoter proximal transcription factor-associated gene expression and super-enhancer-driven transcriptional programs are not well-defined. Some level of their distinct genomic occupancy may suggest a mechanism with specific target gene control. We explored the transcriptional and functional interrelationship between E2F transcription factors and BET transcriptional co-activators in multiple myeloma. Global chromatin analysis reveals distinct regulatory axes for E2F and BETs, with E2F predominantly localized to active gene promoters of growth/proliferation genes and BETs disproportionately at enhancer- regulated tissue specific genes. Depletion of E2F selectively down-regulates its regulatory axis and is generally synergistic with BET inhibition. In vivo, combined inhibition of BETs and E2F strongly reduces tumor growth, implicating E2F as a myeloma dependency that is potently leveraged with BET inhibition.
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Project description:Dynamic transcriptional reprogramming leads to novel immunotherapeutic vulnerabilities in myeloma
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Project description:CDK7 inhibitor, Q901 synergizes with topoisomerase 1 inhibition by disrupting MYC/E2F-driven transcription program
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