Targeting enhancer reprogramming to mitigate MEK inhibitor resistance in preclinical models of advanced ovarian cancer
Targeting enhancer reprogramming to mitigate MEK inhibitor resistance in preclinical models of advanced ovarian cancer
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靶向增强子重编程以减轻晚期卵巢癌临床前模型中的 MEK 抑制剂耐药性
DOI：
10.1172/jci145035
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发表时间：
2021
影响因子：
15.9
通讯作者：
Wa
中科院分区：
文献类型：
--
作者：
Liu Shini;Zou Qiong;Chen Jie-Ping;Yao Xiaosai;Guan Peiyong;Liang Weiting;Deng Peng;Lai Xiaowei;Yin Jiaxin;Chen Jinghong;Chen Rui;Yu Zhaoliang;Xiao Rong;Sun Yichen;Hong Jing Han;Liu Hui;Lu Huaiwu;Chen Jianfeng;Bei Jin-Xin;Koh Joanna;Chan Jason Yongsheng;Wa
卵巢癌的特征是丝裂原活化蛋白激酶(MAPK)的异常激活，这突显了靶向MAPK通路作为一种有吸引力的治疗策略的重要性。然而，MEK抑制剂的临床疗效受到固有或获得性耐药的限制。在这里，我们建立了对MEK抑制剂耐药的患者来源的卵巢癌模型，并证明了对临床批准的MEK抑制剂曲美替尼的耐药性与增强子重新编程有关。我们还发现，增强子失活导致MAPK途径负性调节因子下调，导致结构性ERK激活和对曲美替尼的获得性耐药性。表观遗传化合物筛选发现，HDAC抑制剂可以改变增强子重编程，上调MAPK负性调控因子的表达，导致MAPK持续抑制和曲美替尼耐药逆转。因此，HDAC抑制剂和曲美替尼的组合在体外和体内都显示出协同抗肿瘤作用，包括患者来源的异种移植小鼠模型。这些发现表明，MAPK调节通路的增强子重新编程可能是导致MAPK抑制剂耐药的潜在机制，表观遗传通路和MAPK信号通路的同时靶向可能为晚期卵巢癌提供有效的治疗策略。
Ovarian cancer is characterized by aberrant activation of the mitogen-activated protein kinase (MAPK), highlighting the importance of targeting the MAPK pathway as an attractive therapeutic strategy. However, the clinical efficacy of MEK inhibitors is limited by intrinsic or acquired drug resistance. Here, we established patient-derived ovarian cancer models resistant to MEK inhibitors and demonstrated that resistance to the clinically approved MEK inhibitor trametinib was associated with enhancer reprogramming. We also showed that enhancer decommissioning induced the downregulation of negative regulators of the MAPK pathway, leading to constitutive ERK activation and acquired resistance to trametinib. Epigenetic compound screening uncovered that HDAC inhibitors could alter the enhancer reprogramming and upregulate the expression of MAPK negative regulators, resulting in sustained MAPK inhibition and reversal of trametinib resistance. Consequently, a combination of HDAC inhibitor and trametinib demonstrated a synergistic antitumor effect in vitro and in vivo, including patient-derived xenograft mouse models. These findings demonstrated that enhancer reprogramming of the MAPK regulatory pathway might serve as a potential mechanism underlying MAPK inhibitor resistance and concurrent targeting of epigenetic pathways and MAPK signaling might provide an effective treatment strategy for advanced ovarian cancer.