Bromodomain inhibition targeting BPTF in the treatment of melanoma and other solid tumors

IF 4.2 3区 医学 Q2 ONCOLOGY
Imran Khan, Mohammed Kashani-Sabet
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Abstract

Epigenetic mechanisms have been shown to play an important role in the development of cancer. These include the activation of chromatin remodeling factors in various malignancies, including bromodomain plant homeodomain (PHD) finger transcription factor (BPTF), the largest component of the human nucleosome remodeling factor (NURF). In the last few years, BPTF has been identified as a pro-tumorigenic factor in melanoma, stimulated by research into the molecular mechanisms underlying BPTF function. Developing therapy targeting the BPTF bromodomain would represent a significant advance. Melanoma therapy has been revolutionized by the efficacy of immunotherapeutic and targeted strategies, but the development of drug resistance calls for alternative therapeutic approaches. Recent work has shown both a biomarker as well as functional role for BPTF in melanoma progression and as a possible target for its therapy. BPTF was shown to stimulate the mitogen-activated protein kinase pathway, which is targeted by selective BRAF inhibitors. The advent of small molecule inhibitors that target bromodomain motifs has shown that bromodomains are druggable. By combining the bromodomain inhibitor bromosporine with existing treatments that target mutant BRAF, BPTF targeting has emerged as a novel and promising therapeutic approach for metastatic melanoma. This article summarizes the functional role of BPTF in tumor progression, reviews the clinical experience to date with bromodomain inhibitors, and discusses the promise of BPTF targeting in melanoma and other solid tumors.

Abstract Image

以 BPTF 为靶点的溴化酶抑制剂治疗黑色素瘤和其他实体瘤
表观遗传机制已被证明在癌症的发生发展中起着重要作用。这些机制包括在各种恶性肿瘤中激活染色质重塑因子,其中包括人类核糖体重塑因子(NURF)的最大组成部分--溴代植物同源染色体(PHD)指转录因子(BPTF)。在过去几年中,BPTF 已被确定为黑色素瘤中的促致癌因子,对 BPTF 功能的分子机制的研究也促进了对 BPTF 的研究。开发针对 BPTF 溴链的疗法将是一项重大进展。免疫疗法和靶向疗法的疗效使黑色素瘤的治疗发生了革命性的变化,但耐药性的产生要求采用其他治疗方法。最近的研究表明,BPTF 在黑色素瘤的发展过程中既是一种生物标志物,也是一种功能性角色,还是一种可能的治疗靶点。研究表明,BPTF 能刺激丝裂原活化蛋白激酶通路,而选择性 BRAF 抑制剂正是以该通路为靶点。以溴结构域为靶点的小分子抑制剂的出现表明,溴结构域是可以药物治疗的。通过将溴基团抑制剂溴孢菌素与针对突变型 BRAF 的现有治疗方法相结合,以 BPTF 为靶点的治疗方法已成为治疗转移性黑色素瘤的一种新型且前景广阔的方法。本文总结了 BPTF 在肿瘤进展中的功能性作用,回顾了迄今为止溴链抑制剂的临床经验,并探讨了 BPTF 靶向治疗黑色素瘤和其他实体瘤的前景。
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来源期刊
CiteScore
7.80
自引率
5.00%
发文量
55
审稿时长
12 months
期刊介绍: The Journal''s scope encompasses all aspects of metastasis research, whether laboratory-based, experimental or clinical and therapeutic. It covers such areas as molecular biology, pharmacology, tumor biology, and clinical cancer treatment (with all its subdivisions of surgery, chemotherapy and radio-therapy as well as pathology and epidemiology) insofar as these disciplines are concerned with the Journal''s core subject of metastasis formation, prevention and treatment.
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