<i>MYCL</i> is a target of a BET bromodomain inhibitor, JQ1, on growth suppression efficacy in small cell lung cancer cells

Kato, Fuyumi; Fiorentino, Francesco Paolo; Alibés, Andreu; Perucho, Manuel; Sanchez-Cespedes, Montse; Kohno, Takashi; Yokota, Jun

doi:10.18632/oncotarget.12671

Cited by 49 publications

(43 citation statements)

References 40 publications

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“…The BET family member BRD4 recruits positive transcription elongation factor b (P-TEFb) to promoters and enhancers, releasing RNA polymerase II and initiating transcriptional elongation [64]. JQ1, a BET inhibitor, has been shown to inhibit BRD4 binding at acetylated histones within the MYC promoter and enhancers, decreasing expression of c-, L-, and N-MYC [65][66][67]. JQ1 treatment reduces tumor cell survival and has anti-tumor effects in vitro and in vivo in multiple models [68][69][70][71][72][73].…”

Section: Inhibition Of Transcriptionmentioning

confidence: 99%

Mission Possible: Advances in MYC Therapeutic Targeting in Cancer

Allen-Petersen¹,

Sears²

2019

BioDrugs

134

110

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MYC is a master transcriptional regulator that controls almost all cellular processes. Over the last several decades, researchers have strived to define the context-dependent transcriptional gene programs that are controlled by MYC, as well as the mechanisms that regulate MYC function, in an effort to better understand the contribution of this oncoprotein to cancer progression. There are a wealth of data indicating that deregulation of MYC activity occurs in a large number of cancers and significantly contributes to disease progression, metastatic potential, and therapeutic resistance. Although the therapeutic targeting of MYC in cancer is highly desirable, there remain substantial structural and functional challenges that have impeded direct MYC-targeted drug development and efficacy. While efforts to drug the 'undruggable' may seem futile given these challenges and considering the broad reach of MYC, significant strides have been made to identify points of regulation that can be exploited for therapeutic purposes. These include targeting the deregulation of MYC transcription in cancer through small-molecule inhibitors that induce epigenetic silencing or that regulate the G-quadruplex structures within the MYC promoter. Alternatively, compounds that disrupt the DNA-binding activities of MYC have been the long-standing focus of many research groups, since this method would prevent downstream MYC oncogenic activities regardless of upstream alterations. Finally, proteins involved in the post-translational regulation of MYC have been identified as important surrogate targets to reduce MYC activity downstream of aberrant cell stimulatory signals. Given the complex regulation of the MYC signaling pathway, a combination of these approaches may provide the most durable response, but this has yet to be shown. Here, we provide a comprehensive overview of the different therapeutic strategies being employed to target oncogenic MYC function, with a focus on post-translational mechanisms.

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Section: Inhibition Of Transcriptionmentioning

confidence: 99%

Mission Possible: Advances in MYC Therapeutic Targeting in Cancer

Allen-Petersen¹,

Sears²

2019

BioDrugs

134

110

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“…127 JQ-1 was moreover shown to have antiproliferative effects in SCLC cell lines. 128,129 Interestingly, key targets with reduced expression upon JQ-1 treatment in SCLC cell lines were MYC family members 129 and ASCL1, 130 but currently biomarkers predicting JQ-1 sensitivity in SCLC are lacking. More recently, CHK1 inhibition has been identified as an additional drug target that elicits efficacy specifically in MYCdriven SCLC, 11 suggesting that MYC status is an important determinant of therapeutic response in SCLC.…”

Section: Targeting Myc In Small Cell Lung Cancermentioning

confidence: 99%

Family matters: How MYC family oncogenes impact small cell lung cancer

et al. 2017

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Small cell lung cancer (SCLC) is one of the most deadly cancers and currently lacks effective targeted treatment options. Recent advances in the molecular characterization of SCLC has provided novel insight into the biology of this disease and raises hope for a paradigm shift in the treatment of SCLC. We and others have identified activation of MYC as a driver of susceptibility to Aurora kinase inhibition in SCLC cells and tumors that translates into a therapeutic option for the targeted treatment of MYC-driven SCLC. While MYC shares major features with its paralogs MYCN and MYCL, the sensitivity to Aurora kinase inhibitors is unique for MYC-driven SCLC. In this review, we will compare the distinct molecular features of the 3 MYC family members and address the potential implications for targeted therapy of SCLC.

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“…Loss of BRD4, a bromodomain protein that binds acetylated histones, or its pharmacological inhibition, can cause super enhancer-mediated gene expression to be lost [ 98 ]. In SCLCs, MYCL, one of the three MYC family oncogenes, is often overexpressed and treatment with JQ1, a BET bromodomain inhibitor, considerably decreased cell growth, induced cell cycle arrest and apoptosis, and reduced expression of the three MYC genes [ 99 ].…”

Section: Emt and Epigenetics In Lung Cancermentioning

confidence: 99%

Epigenetic Regulation of the Epithelial to Mesenchymal Transition in Lung Cancer

Roche

Gemmill

Drabkin

2017

Cancers

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Lung cancer is the leading cause of cancer deaths worldwide. It is an aggressive and devastating cancer because of metastasis triggered by enhanced migration and invasion, and resistance to cytotoxic chemotherapy. The epithelial to mesenchymal transition (EMT) is a fundamental developmental process that is reactivated in wound healing and a variety of diseases including cancer where it promotes migration/invasion and metastasis, resistance to treatment, and generation and maintenance of cancer stem cells. The induction of EMT is associated with reprogramming of the epigenome. This review focuses on major mechanisms of epigenetic regulation mainly in lung cancer with recent data on EZH2 (enhancer of zeste 2 polycomb repressive complex 2 subunit ), the catalytic subunit of the PRC2 (Polycomb Group PcG), that behaves as an oncogene in lung cancer associated with gene repression, non-coding RNAs and the epitranscriptome.

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MYCL is a target of a BET bromodomain inhibitor, JQ1, on growth suppression efficacy in small cell lung cancer cells

Cited by 49 publications

References 40 publications

Mission Possible: Advances in MYC Therapeutic Targeting in Cancer

Mission Possible: Advances in MYC Therapeutic Targeting in Cancer

Family matters: How MYC family oncogenes impact small cell lung cancer

Epigenetic Regulation of the Epithelial to Mesenchymal Transition in Lung Cancer

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