CDK9-mediated transcription elongation is required for MYC addiction in hepatocellular carcinoma

Huang, Chun‐Hao; Lujambio, Amaia; Zuber, Johannes; Tschaharganeh, Darjus F.; Doran, Michael G.; Evans, Michael J.; Kitzing, Thomas; Zhu, Nan; Stanchina, Elisa de; Sawyers, Charles L.; Armstrong, Scott A.; Lewis, Jason S.; Sherr, Charles J.; Lowe, Scott W.

doi:10.1101/gad.244368.114

Cited by 177 publications

(204 citation statements)

References 71 publications

(99 reference statements)

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“…Human PDAC cells as well as autochthonous PDAC models indicate that BET inhibition also provokes MYC down-regulation and suppression of pancreatic tumorigenesis in conjunction with HDAC inhibition (Mazur et al 2015). The attractiveness of MYC as a target also stems from the observation that MYC binds to promoter regions of active genes and causes transcriptional "amplification" (Lin et al 2012;Nie et al 2012), which appears to engender vulnerability to blockade of transcriptional elongation by targeting CDK9, a key component of the transcription elongation complex (Huang et al 2014). Interestingly, a recent study showed that suppression of MYC results in induction of PGC1α and increased mitochondrial respiration, which functions to sustain the PDAC CSC population, implicating the utility of targeting mitochondria oxidative phosphorylation (OXPHOS) in combination with MYC inhibition (Sancho et al 2015).…”

Section: Additional Amplified Oncogenesmentioning

confidence: 99%

Genetics and biology of pancreatic ductal adenocarcinoma

et al. 2016

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With 5-year survival rates remaining constant at 6% and rising incidences associated with an epidemic in obesity and metabolic syndrome, pancreatic ductal adenocarcinoma (PDAC) is on track to become the second most common cause of cancer-related deaths by 2030. The high mortality rate of PDAC stems primarily from the lack of early diagnosis and ineffective treatment for advanced tumors. During the past decade, the comprehensive atlas of genomic alterations, the prominence of specific pathways, the preclinical validation of such emerging targets, sophisticated preclinical model systems, and the molecular classification of PDAC into specific disease subtypes have all converged to illuminate drug discovery programs with clearer clinical path hypotheses. A deeper understanding of cancer cell biology, particularly altered cancer cell metabolism and impaired DNA repair processes, is providing novel therapeutic strategies that show strong preclinical activity. Elucidation of tumor biology principles, most notably a deeper understanding of the complexity of immune regulation in the tumor microenvironment, has provided an exciting framework to reawaken the immune system to attack PDAC cancer cells. While the long road of translation lies ahead, the path to meaningful clinical progress has never been clearer to improve PDAC patient survival. Pancreatic ductal adenocarcinoma (PDAC) pathogenesisOn gross inspection, PDAC presents as a poorly demarcated, firm white-yellow mass, with the surrounding nonmalignant pancreas typically showing atrophy, fibrosis, and dilated ducts due to the obstructive effects of expanding carcinoma. Microscopically, these neoplasms vary from well-differentiated gland-forming carcinomas to poorly differentiated "sarcomatoid" carcinomas diagnosed only upon immunolabeling due to predominant mesenchymal features (Hruban et al. 2007). PDAC evolves from well-defined precursor lesions that, in the context of their genetic features, define the genetic progression model of pancreatic carcinogenesis (Yachida et al. 2010). Early disease histology manifests as several distinct types of precursor lesions-the most common are microscopic pancreatic intraepithelial neoplasia (PanIN), followed by the macroscopic cysts; namely, the intraductal papillary mucinous neoplasm (IPMN) and mucinous cystic neoplasm (MCN) (Matthaei et al. 2011). Since most PDAC cases become clinically apparent at advanced stages, major opportunities to reduce mortality rest with diagnostics and treatments that would enable the reliable identification and elimination of high-risk precursor lesions. Thus, the identification of these precursor lesions has provided an essential framework to define the genomic features that drive progression to advanced disease and develop effective screening and targeted therapeutics for earlier stage disease (Eser et al. 2011).The noninvasive PanIN lesions were formerly classified into three grades according to the extent of cytological and architectural atypia: PanIN1A (flat lesion) and PanIN1B (micropapillary...

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Section: Additional Amplified Oncogenesmentioning

confidence: 99%

Genetics and biology of pancreatic ductal adenocarcinoma

et al. 2016

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“…A recent RNA interference screen in a MYC-driven hepatocellular carcinoma found CDK9 as a target and showed that CDK9 inhibitors blocked proliferation of MYC-amplified tumors (25). Treatment of mixed-lineage leukemias with CDK9 inhibitors reduced MYC expression (26), suggesting that MYC is a target of CDK9-mediated transcriptional control.…”

Section: Cdk9 Targeting Decreases Btic Growth and Self-renewalmentioning

confidence: 99%

RBPJ maintains brain tumor–initiating cells through CDK9-mediated transcriptional elongation

Xie¹,

Wu²,

Kim³

et al. 2016

Journal of Clinical Investigation

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“…Depending on tissue-specific signaling pathways, CDK9 responds to cytokines, including the tumor necrosis factor and interleukin-6 (MacLachlan et al 1998, Bellan et al 2004. Studies on different human cancers like lymphoma (Bettayeb et al 2007, Gregory et al 2015, neuroblastoma (De Falco et al 2005), PCa and several instances of hematopoietic malignancies (Huang et al 2014) revealed that CDK9-related pathways are deregulated, indicating that CDK9 hyperactivity may promote the expression of anti-apoptotic factors and induce proliferation (Jin et al 2015). Even though CDK9 has a crucial role in both normal and cancer cells, overexpression of short half-lived anti-apoptotic factors like MCL-1, BCL-2 and Figure 1 Regulation of transcription by CDK9.…”

Section: Biology Of Cdk9mentioning

confidence: 99%

Targeting CDK9: a promising therapeutic opportunity in prostate cancer

Rahaman

Kumarasiri

Mekonnen

et al. 2016

Endocrine-Related Cancer

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Cyclin-dependent kinase 9 (CDK9) is a key transcriptional regulator and a lucrative target for cancer treatment. Targeting CDK9 can effectively confine the hyperactivity of androgen receptor and the constitutive expression of anti-apoptotic proteins; both being main causes of prostate cancer (PCa) development and progression. In castrate-resistant PCa, traditional therapies that only target androgen receptor (AR) have become obsolete due to reprograming in AR activity to make the cells independent of androgen. CDK9 inhibitors may provide a new and better therapeutic opportunity over traditional treatment options by targeting both androgen receptor activity and antiapoptotic proteins, improving the chances of positive outcomes, especially in patients with the advanced disease. This review focuses on biological functions of CDK9, its involvement with AR and the potential for therapeutic opportunities in PCa treatment.

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CDK9-mediated transcription elongation is required for MYC addiction in hepatocellular carcinoma

Cited by 177 publications

References 71 publications

Genetics and biology of pancreatic ductal adenocarcinoma

Genetics and biology of pancreatic ductal adenocarcinoma

RBPJ maintains brain tumor–initiating cells through CDK9-mediated transcriptional elongation

Targeting CDK9: a promising therapeutic opportunity in prostate cancer

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