BET抑制剂通过抑制STAT3信号通路参与舒尼替尼协同治疗黑素瘤的机制研究

传统BET抑制剂对黑素瘤疗效欠佳。我们团队前期开发了一种新型BET抑制剂NHWD-870，可以通过BRD4/HIF1α/CSF1及BRD4/NFKB2/SPP1轴抑制黑素瘤的进展。目前NHWD-870已获国内1.1类原创新药批件，正启动I期临床试验，但BET抑制剂联合用药方案有待探索。我们前期研究发现：BET抑制剂与舒尼替尼可以协同治疗黑素瘤，BET抑制剂可下调STAT3信号通路，且敲降STAT3可以增强舒尼替尼治疗黑素瘤的敏感性。为此我们提出假说：BET抑制剂通过抑制STAT3信号通路，从而增敏舒尼替尼疗效，达到协同治疗黑素瘤的效果。本课题拟在细胞、动物层面，应用高通量测序、STAT3敲降及过表达、IL-6的中和抗体等技术，探讨BET抑制剂与舒尼替尼治疗黑素瘤的协同效果及具体机制，为BET抑制剂在黑素瘤中的基础及转化研究奠定基础。

The traditional BET inhibitors are ineffective in melanoma. We previously developed a novel BET inhibitor, NHWD-870, which could inhibit the progression of melanoma through BRD4/HIF1α/CSF1 and BRD4/NFKB2/SPP1 axes. NHWD-870 has been approved as a class 1.1 new drug in China and is starting phase I clinical trial. However, the combination therapy of BET inhibitors remains to be explored. We found that BET inhibitors and sunitinib had a synergistic effect on melanoma; BET inhibitors could downregulate STAT3 signaling pathway, and the down-regulation of STAT3 could enhance the sensitivity of melanoma to sunitinib. Therefore, we proposed the hypothesis that BET inhibitors sensitized melanoma to sunitinib by inhibiting the STAT3 signaling pathway and finally achieved synergistic effects. This project aims to explore the specific mechanism of BET inhibitors and sunitinib in the synergistic treatment of melanoma by using high-throughput sequencing, STAT3 knockdown and overexpression, and neutralizing antibody of IL-6 in vitro and vivo. Our study will lay a foundation for the basic and translational research of BET inhibitors in melanoma.