The BRD9/7 Inhibitor TP-472 Blocks Melanoma Tumor Growth by Suppressing ECM-Mediated Oncogenic Signaling and Inducing Apoptosis.

The BRD9/7 Inhibitor TP-472 Blocks Melanoma Tumor Growth by Suppressing ECM-Mediated Oncogenic Signaling and Inducing Apoptosis.

Melanoma is an aggressive form of skin cancer and the leading cause of skin cancer-related deaths. Current therapies, including those targeting oncogenic pathways and immunotherapies, provide therapeutic benefits to only a subset of melanoma patients. Therefore, more options for therapeutic interventions are needed. Epigenetic alterations play an important role in tumor development and progression. In this study, we identified that TP-472 a small molecule inhibitor of BRD7/9 blocks melanoma tumor growth in cell cultures and in mouse models of melanoma growth. Further studies revealed that TP-472 downregulates cancer-promoting signaling pathways and induces cell death. Thus, this study identifies TP-472 as a potentially useful therapeutic agent for melanoma therapy. Melanoma accounts for the majority of all skin cancer-related deaths and only 1/3rd of melanoma patients with distal metastasis survive beyond five years. However, current therapies including BRAF/MEK targeted therapies or immunotherapies only benefit a subset of melanoma patients due to the emergence of intrinsic or extrinsic resistance mechanisms. Effective treatment of melanoma will thus require new and more effective therapeutic agents. Towards the goal of identifying new therapeutic agents, we conducted an unbiased, druggable epigenetic drug screen using a library of 32 epigenetic inhibitors obtained from the Structural Genome Consortium that targets proteins encoding for epigenetic regulators. This chemical genetic screening identified TP-472, which targets bromodomain-7/9, as the strongest inhibitor of melanoma growth in both short- and long-term survival assays and in mouse models of melanoma tumor growth. Mechanistically, using a transcriptome-wide mRNA sequencing profile we identified TP-472 treatment downregulates genes encoding various extracellular matrix (ECM) proteins, including integrins, collagens, and fibronectins. Reactome-based functional pathway analyses revealed that many of the ECM proteins are involved in extracellular matrix interactions required for cancer cell growth and proliferation. TP-472 treatment also upregulated several pro-apoptotic genes that can inhibit melanoma growth. Collectively, our results identify BRD7/9 inhibitor TP-472 as a potentially useful therapeutic agent for melanoma therapy.

黑色素瘤是一种侵袭性皮肤癌，是皮肤癌相关死亡的主要原因。目前的疗法，包括那些针对致癌通路的疗法和免疫疗法，仅对一部分黑色素瘤患者有治疗效果。因此，需要更多的治疗干预选择。表观遗传改变在肿瘤的发生和发展中起着重要作用。在这项研究中，我们发现TP - 472（一种BRD7/9的小分子抑制剂）在细胞培养和黑色素瘤生长的小鼠模型中抑制黑色素瘤肿瘤生长。进一步的研究表明，TP - 472下调促进癌症的信号通路并诱导细胞死亡。因此，这项研究确定TP - 472是一种对黑色素瘤治疗可能有用的治疗药物。 黑色素瘤在所有皮肤癌相关死亡中占大多数，只有三分之一的远端转移黑色素瘤患者能存活超过五年。然而，由于内在或外在耐药机制的出现，目前的疗法，包括BRAF/MEK靶向疗法或免疫疗法，仅对一部分黑色素瘤患者有益。因此，黑色素瘤的有效治疗将需要新的、更有效的治疗药物。为了确定新的治疗药物这一目标，我们使用从结构基因组联盟获得的一个包含32种表观遗传抑制剂的文库进行了无偏向的、可成药的表观遗传药物筛选，这些抑制剂针对编码表观遗传调节因子的蛋白质。这种化学遗传学筛选确定了TP - 472（其靶向含溴结构域7/9），它在短期和长期存活试验以及黑色素瘤肿瘤生长的小鼠模型中是对黑色素瘤生长抑制作用最强的药物。从机制上讲，通过全转录组mRNA测序图谱，我们发现TP - 472治疗下调编码各种细胞外基质（ECM）蛋白的基因，包括整合素、胶原蛋白和纤连蛋白。基于Reactome的功能通路分析表明，许多ECM蛋白参与癌细胞生长和增殖所需的细胞外基质相互作用。TP - 472治疗还上调了几个促凋亡基因，这些基因可以抑制黑色素瘤生长。总之，我们的结果确定BRD7/9抑制剂TP - 472是一种对黑色素瘤治疗可能有用的治疗药物。