Targeting enhancer reprogramming to mitigate MEK inhibitor resistance in preclinical models of advanced ovarian cancer

• Published in: The Journal of clinical investigation 2021-10, Vol.131 (20), p.1-15
• Main Authors: 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, Wang, Baohua, Kang, Tiebang, Yu, Qiang, Teh, Bin-Tean, Liu, Jihong, Xiong, Ying, Tan, Jing
• Format: Article
• Language: English
• Subjects: Animal models; Animals; Antitumor activity; Biomedical research; Cancer therapies; Cell Line, Tumor; Cellular signal transduction; Colorectal cancer; Disease Models, Animal; Drug dosages; Drug resistance; Drug Resistance, Neoplasm; Drug targeting; Drug therapy; Enhancer Elements, Genetic; Enzyme inhibitors; Epigenetic inheritance; Epigenetics; Extracellular signal-regulated kinase; Female; Gene amplification; Genetic aspects; Health aspects; Histone deacetylase; Histone Deacetylase Inhibitors - pharmacology; Humans; Kinases; MAP kinase; MAP Kinase Signaling System - physiology; MEK inhibitors; Melanoma; Mice; Mitogen-Activated Protein Kinase Kinases - antagonists & inhibitors; Mitogen-activated protein kinases; Mutation; Ovarian cancer; Ovarian Neoplasms - drug therapy; Patients; Pharmacology, Experimental; Phosphorylation; Protein kinase; Protein Kinase Inhibitors - therapeutic use; Proteins; Pyridones - pharmacology; Pyrimidinones - pharmacology; Xenografts
• ISSN: 1558-8238; 0021-9738; 1558-8238
• DOI: 10.1172/JCI145035

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.