1. Epigenetic alterations of testicular germ cell tumours
Iris E Ertl, Dafina Ilijazi, Melanie R Hassler, Ursula Lemberger, Shahrok F Shariat Curr Opin Urol . 2020 Mar;30(2):264-270. doi: 10.1097/MOU.0000000000000724.
Purpose of review:Testicular germ cell tumours (TGCTs) exhibit, in contrast to other cancer types, a relatively low mutational burden. However, numerous epigenetic alterations have been shown to impact TGCT. In this review, we summarize the most relevant findings of the past 2 years.Recent findings:Recent studies focused on the functions of microRNAs and the impact of aberrant DNA methylation. Moreover, several epigenetic drugs with antineoplastic effects in TGCTs were identified.Summary:Aberrant DNA methylation and differentially expressed microRNAs have an important effect on TGCT pathogenesis. Moreover, differential DNA methylation patterns were found to be specific for different TGCT subtypes. Various microRNAs, such as miR-371a-3p, were found to be highly sensitive and specific biomarkers for TGCT. The epigenetic drugs guadecitabine, animacroxam, and JQ1 showed promising effects on TGCT in preclinical in-vivo and in-vitro studies.
2. Activity of BET-proteolysis targeting chimeric (PROTAC) compounds in triple negative breast cancer
Juan Carlos Montero, Miguel Burgos, Mónica Gómez-Juárez, Cristina Nieto-Jimenez, Azucena Esparís-Ogando, Eva M Galán-Moya, Alberto Ocaña, María Del Mar Noblejas-López, Atanasio Pandiella J Exp Clin Cancer Res . 2019 Aug 30;38(1):383. doi: 10.1186/s13046-019-1387-5.
Background:Triple negative breast cancer (TNBC) is an incurable disease where novel therapeutic strategies are needed. Proteolysis targeting chimeric (PROTAC) are novel compounds that promote protein degradation by binding to an ubiquitin ligase. In this work, we explored the antitumoral activity of two novel BET-PROTACs, MZ1 and ARV-825, in TNBC, ovarian cancer and in a BET inhibitor resistant model.Methods:OVCAR3, SKOV3, BT549, MDA-MB-231 cell lines and the JQ1 resistant cell line MDA-MB-231R were evaluated. MTTs, colony-forming assay, three-dimensional cultures in matrigel, flow cytometry, and western blots were performed to explore the anti-proliferative effect and biochemical mechanism of action of MZ1 and ARV-825. In vivo studies included BALB/c nu/nu mice engrafted with MDA-MB-231R cells.Results:The BET-PROTACs MZ1 and ARV-825 efficiently downregulated the protein expression levels of the BET protein BRD4, in MDA-MB-231 and MDA-MB-231R. MZ1 and ARV-825 also showed an antiproliferative effect on sensitive and resistant cells. This effect was corroborated in other triple negative (BT549) and ovarian cancer (SKOV3, OVCAR3) cell lines. MZ1 provoked G2/M arrest in MDA-MB-231. In addition, a profound effect on caspase-dependent apoptosis was observed in both sensitive and resistant cells. No synergistic activity was observed when it was combined with docetaxel, cisplatin or olaparib. Finally, in vivo administration of MZ1 rescued tumor growth in a JQ1-resistant xenograft model, reducing the expression levels of BRD4.Conclusions:Using both in vitro and in vivo approaches, we describe the profound activity of BET-PROTACs in parental and BETi-resistant TNBC models. This data provides options for further clinical development of these agents in TNBC.
3. Prostate cancer-associated SPOP mutations confer resistance to BET inhibitors through stabilization of BRD4
Kouhei Shimizu, Mark A Rubin, Shangqian Wang, Qing Zhong, Hiroyuki Inuzuka, Levi A Garraway, Andrew H Beck, Ling Huang, Wenyi Wei, Liewei Wang, Xiaoning Li, Jianping Guo, Ting Chen, Wei Zhang, Francisco Beca, Jinfang Zhang, Xiangpeng Dai, Lorenz Buser, Peter J Wild, Kwok-Kin Wong, James E Bradner, Yu Chen, Pengda Liu, Jun Qi, Jiaoti Huang, Senthil K Muthuswamy, Mirjam Blattner, Christopher E Barbieri, Dennis L Buckley, Shengwu Liu, Wenjian Gan, Divya Vasudevan Nat Med . 2017 Sep;23(9):1063-1071. doi: 10.1038/nm.4378.
The bromodomain and extraterminal (BET) family of proteins comprises four members-BRD2, BRD3, BRD4 and the testis-specific isoform BRDT-that largely function as transcriptional coactivators and play critical roles in various cellular processes, including the cell cycle, apoptosis, migration and invasion. BET proteins enhance the oncogenic functions of major cancer drivers by elevating the expression of these drivers, such as c-Myc in leukemia, or by promoting the transcriptional activities of oncogenic factors, such as AR and ERG in prostate cancer. Pathologically, BET proteins are frequently overexpressed and are clinically linked to various types of human cancer; they are therefore being pursued as attractive therapeutic targets for selective inhibition in patients with cancer. To this end, a number of bromodomain inhibitors, including JQ1 and I-BET, have been developed and have shown promising outcomes in early clinical trials. Although resistance to BET inhibitors has been documented in preclinical models, the molecular mechanisms underlying acquired resistance are largely unknown. Here we report that cullin-3SPOPearmarks BET proteins, including BRD2, BRD3 and BRD4, for ubiquitination-mediated degradation. Pathologically, prostate cancer-associated SPOP mutants fail to interact with and promote the degradation of BET proteins, leading to their elevated abundance in SPOP-mutant prostate cancer. As a result, prostate cancer cell lines and organoids derived from individuals harboring SPOP mutations are more resistant to BET-inhibitor-induced cell growth arrest and apoptosis. Therefore, our results elucidate the tumor-suppressor role of SPOP in prostate cancer in which it acts as a negative regulator of BET protein stability and also provide a molecular mechanism for resistance to BET inhibitors in individuals with prostate cancer bearing SPOP mutations.
