BET protein inhibitor JQ1 attenuates Myc-amplified MCC tumor growth in vivo.

Merkel cell carcinoma (MCC) is an aggressive neuroendocrine tumor of the skin currently with no cure. In this study, we have first demonstrated that c-Myc overexpression is common in MCC. By targeting c-Myc, bromodomain inhibitors have demonstrated antitumor efficacy in several preclinical human cancer models. Thus, we interrogated the role of c-Myc inhibition in MCC with c-Myc amplification by using the BET inhibitor JQ1. We have uncovered that c-Myc can be regulated by JQ1 in MCC cells with pathologic c-Myc activation. Moreover, JQ1 potently abrogates c-Myc expression in MCC cells and causes marked G1 cell-cycle arrest. Mechanistically, JQ1-induced cell-cycle arrest coincides with downregulation of cyclin D1 and upregulation of p21, p27, and p57, whereas JQ1 exerts no effect on apoptosis in MCC cells. Further knockdown of p21, p27, or p57 by shRNA partially protects cells from JQ1-induced cell-cycle arrest. In addition, c-Myc knockdown by shRNA generates significant cell-cycle arrest, suggesting that c-Myc overexpression plays a role in MCC pathogenesis. Most importantly, JQ1 significantly attenuates tumor growth in xenograft MCC mouse models. Our results provide initial evidence, indicating the potential clinical utility of BET protein inhibitors in the treatment of MCC with pathologic activation of c-Myc.

Shao Q ，Kannan A ，Lin Z ，Stack BC Jr ，Suen JY ，Gao L ... -  《-》

BET bromodomain inhibition of MYC-amplified medulloblastoma.

MYC-amplified medulloblastomas are highly lethal tumors. Bromodomain and extraterminal (BET) bromodomain inhibition has recently been shown to suppress MYC-associated transcriptional activity in other cancers. The compound JQ1 inhibits BET bromodomain-containing proteins, including BRD4. Here, we investigate BET bromodomain targeting for the treatment of MYC-amplified medulloblastoma. We evaluated the effects of genetic and pharmacologic inhibition of BET bromodomains on proliferation, cell cycle, and apoptosis in established and newly generated patient- and genetically engineered mouse model (GEMM)-derived medulloblastoma cell lines and xenografts that harbored amplifications of MYC or MYCN. We also assessed the effect of JQ1 on MYC expression and global MYC-associated transcriptional activity. We assessed the in vivo efficacy of JQ1 in orthotopic xenografts established in immunocompromised mice. Treatment of MYC-amplified medulloblastoma cells with JQ1 decreased cell viability associated with arrest at G1 and apoptosis. We observed downregulation of MYC expression and confirmed the inhibition of MYC-associated transcriptional targets. The exogenous expression of MYC from a retroviral promoter reduced the effect of JQ1 on cell viability, suggesting that attenuated levels of MYC contribute to the functional effects of JQ1. JQ1 significantly prolonged the survival of orthotopic xenograft models of MYC-amplified medulloblastoma (P < 0.001). Xenografts harvested from mice after five doses of JQ1 had reduced the expression of MYC mRNA and a reduced proliferative index. JQ1 suppresses MYC expression and MYC-associated transcriptional activity in medulloblastomas, resulting in an overall decrease in medulloblastoma cell viability. These preclinical findings highlight the promise of BET bromodomain inhibitors as novel agents for MYC-amplified medulloblastoma.

Bandopadhayay P ，Bergthold G ，Nguyen B ，Schubert S ，Gholamin S ，Tang Y ，Bolin S ，Schumacher SE ，Zeid R ，Masoud S ，Yu F ，Vue N ，Gibson WJ ，Paolella BR ，Mitra SS ，Cheshier SH ，Qi J ，Liu KW ，Wechsler-Reya R ，Weiss WA ，Swartling FJ ，Kieran MW ，Bradner JE ，Beroukhim R ，Cho YJ ... -  《-》

Targeting c-Myc: JQ1 as a promising option for c-Myc-amplified esophageal squamous cell carcinoma.

c-Myc amplification-induced cell cycle dysregulation is a common cause for esophageal squamous cell carcinoma (ESCC), but no approved targeted drug is available so far. The bromodomain inhibitor JQ1, which targets c-Myc, exerts anti-tumor activity in multiple cancers. However, the role of JQ1 in ESCC remains unknown. In this study, we reported that JQ1 had potent anti-proliferative effects on ESCC cells in both time- and dose-dependent manners by inducing cell cycle arrest at G1 phase, cell apoptosis, and the mesenchymal-epithelial transition. Follow-up studies revealed that both c-Myc/cyclin/Rb and PI3K/AKT signaling pathways were inactivated by JQ1, as indicated by the downregulation of c-Myc, cyclin A/E, and phosphorylated Rb, AKT and S6. Tumor suppression induced by JQ1 in c-Myc amplified or highly expressed xenografts was higher than that in xenografts with low expression, suggesting its potential role in prediction. In conclusion, targeting c-Myc by JQ1 could cause significant tumor suppression in ESCC both in vitro and in vivo. Also, c-Myc amplification or high expression might serve as a potential biomarker and provide a promising therapeutic option for ESCC.

Wang J ，Liu Z ，Wang Z ，Wang S ，Chen Z ，Li Z ，Zhang M ，Zou J ，Dong B ，Gao J ，Shen L ... -  《-》

The BET Bromodomain Inhibitor JQ1 Suppresses Chondrosarcoma Cell Growth via Regulation of YAP/p21/c-Myc Signaling.

Chondrosarcoma, the second-most frequent primary bone malignancy, is generally more resistant to conventional chemotherapy and radiotherapy. Therefore, the development of an effective adjuvant therapy is necessary. Recently, targeting the epigenetic regulator such as bromodomain and extraterminal domain (BET) proteins has achieved great success. For instance, the bromodomain inhibitor JQ1 has been shown to inhibit the growth of several cancer cells both in vitro and in vivo. Herein, we demonstrated that JQ1 significantly inhibited chondrosarcoma cell growth and colony formation. JQ1 also induced marked G1-phase cell cycle arrest coincided with the up-regulation of p21WAF1/CIP1 , p27Kip1 , and Cyclin D1 expression, and the down-regulation of Cyclin E2 expression. Moreover, JQ1 induced the premature senescence of SW 1353 cells, and that prolong treatment of JQ1 caused cell apoptosis. Mechanistically, the JQ1-induced cell growth inhibition was correlated with the suppression of c-Myc and Bcl-xL, which are the prime genes for cell cycle control and anti-apoptosis. Furthermore, we demonstrated that p21 negatively regulated the expression of c-Myc and Bcl-xL upon JQ1 treatment, and that the growth inhibition of SW 1353 and Hs 819.T cells and induction of p21 were predominantly regulated by the LATS1/YAP signaling but not through a p53-dependent manner. In conclusion, we disclosed a novel mechanism that JQ1 inhibits cell proliferation, induces cell senescence and apoptosis of chondrosarcoma cells through the regulation of the YAP/p21/c-Myc/Bcl-xL signaling axis. J. Cell. Biochem. 118: 2182-2192, 2017. © 2017 Wiley Periodicals, Inc.

Zhang HT ，Gui T ，Sang Y ，Yang J ，Li YH ，Liang GH ，Li T ，He QY ，Zha ZG ... -  《-》

Disruption of BRD4 at H3K27Ac-enriched enhancer region correlates with decreased c-Myc expression in Merkel cell carcinoma.

Sengupta D ，Kannan A ，Kern M ，Moreno MA ，Vural E ，Stack B Jr ，Suen JY ，Tackett AJ ，Gao L ... -  《-》