Peng Ueihuei, Wang Zhihao, Pei Sa, Ou Yunchao, Hu Pengchao, Liu Wanhong, Song Jiquan
Department of Dermatology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China.
School of Basic Medical Sciences, Wuhan University, Wuhan, Hubei 430071, P.R. China.
Oncol Rep. 2017 Feb;37(2):1270-1276. doi: 10.3892/or.2016.5340. Epub 2016 Dec 28.
BRAFV600E mutation is found in ~50% of melanoma patients and BRAFV600E kinase activity inhibitor, vemurafenib, has achieved a remarkable clinical response rate. However, most patients treated with vemurafenib eventually develop resistance. Overcoming primary and secondary resistance to selective BRAF inhibitors remains one of the most critically compelling challenges for these patients. HDAC6 has been shown to confer resistance to chemotherapy in several types of cancer. Few studies focused on the role of HDAC6 in vemurafenib resistance. Here we showed that overexpression of HDAC6 confers resistance to vemurafenib in BRAF-mutant A375 cells. ACY-1215, a selective HDAC6 inhibitor, inhibits the proliferation and induces the apoptosis of A375 cells. Moreover, ACY-1215 sensitizes A375 cells to vemurafenib induced cell proliferation inhibition and apoptosis induction, which occur partly through induction of endoplasmic reticulum (ER) stress and inactivation of extracellular signal-regulated kinase (ERK). Taken together, our results suggest that the inhibition of HDAC6 may be a promising strategy for the treatment of melanoma and overcoming resistance to vemurafenib.
约50%的黑色素瘤患者存在BRAFV600E突变，BRAFV600E激酶活性抑制剂维莫非尼已取得显著的临床缓解率。然而，大多数接受维莫非尼治疗的患者最终会产生耐药性。克服对选择性BRAF抑制剂的原发性和继发性耐药性仍然是这些患者面临的最严峻且迫切的挑战之一。已有研究表明，HDAC6在多种癌症中赋予化疗耐药性。很少有研究关注HDAC6在维莫非尼耐药中的作用。在此我们表明，HDAC6的过表达赋予BRAF突变的A375细胞对维莫非尼的耐药性。选择性HDAC6抑制剂ACY-1215可抑制A375细胞的增殖并诱导其凋亡。此外，ACY-1215使A375细胞对维莫非尼诱导的细胞增殖抑制和凋亡诱导敏感，这部分是通过诱导内质网（ER）应激和细胞外信号调节激酶（ERK）失活实现的。综上所述，我们的结果表明，抑制HDAC6可能是治疗黑色素瘤和克服对维莫非尼耐药性的一种有前景的策略。
