Bernasconi Elena, Gaudio Eugenio, Lejeune Pascale, Tarantelli Chiara, Cascione Luciano, Kwee Ivo, Spriano Filippo, Rinaldi Andrea, Mensah Afua A, Chung Elaine, Stathis Anastasios, Siegel Stephan, Schmees Norbert, Ocker Matthias, Zucca Emanuele, Haendler Bernard, Bertoni Francesco
Università della Svizzera italiana (USI), Institute of Oncology Research (IOR), Bellinzona, Switzerland.
Drug Discovery, Bayer AG, Berlin, Germany.
Br J Haematol. 2017 Sep;178(6):936-948. doi: 10.1111/bjh.14803. Epub 2017 Jun 27.
The epigenome is often deregulated in cancer and treatment with inhibitors of bromodomain and extra-terminal proteins, the readers of epigenetic acetylation marks, represents a novel therapeutic approach. Here, we have characterized the anti-tumour activity of the novel bromodomain and extra-terminal (BET) inhibitor BAY 1238097 in preclinical lymphoma models. BAY 1238097 showed anti-proliferative activity in a large panel of lymphoma-derived cell lines, with a median 50% inhibitory concentration between 70 and 208 nmol/l. The compound showed strong anti-tumour efficacy in vivo as a single agent in two diffuse large B cell lymphoma models. Gene expression profiling showed BAY 1238097 targeted the NFKB/TLR/JAK/STAT signalling pathways, MYC and E2F1-regulated genes, cell cycle regulation and chromatin structure. The gene expression profiling signatures also highly overlapped with the signatures obtained with other BET Bromodomain inhibitors and partially overlapped with HDAC-inhibitors, mTOR inhibitors and demethylating agents. Notably, BAY 1238097 presented in vitro synergism with EZH2, mTOR and BTK inhibitors. In conclusion, the BET inhibitor BAY 1238097 presented promising anti-lymphoma preclinical activity in vitro and in vivo, mediated by the interference with biological processes driving the lymphoma cells. Our data also indicate the use of combination schemes targeting EZH2, mTOR and BTK alongside BET bromodomains.
表观基因组在癌症中常常失调，使用溴结构域和额外末端蛋白（表观遗传乙酰化标记的读取器）抑制剂进行治疗代表了一种新的治疗方法。在此，我们在临床前淋巴瘤模型中对新型溴结构域和额外末端（BET）抑制剂BAY 1238097的抗肿瘤活性进行了表征。BAY 1238097在大量淋巴瘤衍生细胞系中显示出抗增殖活性，50%抑制浓度中位数在70至208 nmol/l之间。该化合物在两种弥漫性大B细胞淋巴瘤模型中作为单一药物在体内显示出强大的抗肿瘤功效。基因表达谱分析表明BAY 1238097靶向NFKB/TLR/JAK/STAT信号通路、MYC和E2F1调控的基因、细胞周期调控和染色质结构。基因表达谱特征也与其他BET溴结构域抑制剂获得的特征高度重叠，并与HDAC抑制剂、mTOR抑制剂和去甲基化剂部分重叠。值得注意的是，BAY 1238097在体外与EZH2、mTOR和BTK抑制剂表现出协同作用。总之，BET抑制剂BAY 1238097在体外和体内均呈现出有前景的抗淋巴瘤临床前活性，这是通过干扰驱动淋巴瘤细胞的生物学过程介导的。我们的数据还表明可将靶向EZH2、mTOR和BTK的联合方案与BET溴结构域一起使用。
