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.

中文翻译：

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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 MEK 抑制剂的耐药性

卵巢癌的特征是丝裂原活化蛋白激酶 (MAPK) 的异常激活，突出了靶向 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内在或获得性耐药性的限制。在这里，我们建立了对 MEK 抑制剂耐药的患者衍生卵巢癌模型，并证明对临床批准的 MEK 抑制剂曲美替尼的耐药与增强子重编程有关。我们还表明，增强子停用诱导 MAPK 途径负调节因子的下调，导致组成型 ERK 激活和对曲美替尼的获得性耐药。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并上调 MAPK 负调节因子的表达，从而导致持续的 MAPK 抑制和逆转曲美替尼的耐药性。因此，HDAC 抑制剂和曲美替尼的组合在体外和体内表现出协同抗肿瘤作用，包括来自患者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编程可能是 MAPK 抑制剂耐药的潜在机制，同时靶向表观遗传通路和 MAPK 信号通路可能为晚期卵巢癌提供有效的治疗策略。HDAC抑制剂和曲美替尼的组合在体外和体内显示出协同抗肿瘤作用，包括来自患者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编程可能是 MAPK 抑制剂耐药的潜在机制，同时靶向表观遗传通路和 MAPK 信号通路可能为晚期卵巢癌提供有效的治疗策略。HDAC抑制剂和曲美替尼的组合在体外和体内显示出协同抗肿瘤作用，包括来自患者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编程可能是 MAPK 抑制剂耐药的潜在机制，同时靶向表观遗传通路和 MAPK 信号通路可能为晚期卵巢癌提供有效的治疗策略。