Targeting enhancer reprogramming to mitigate MEK inhibitor resistance in preclinical models of advanced ovarian cancer
Shini Liu, … , Ying Xiong, Jing Tan
Shini Liu, … , Ying Xiong, Jing Tan
Published August 31, 2021
Citation Information: J Clin Invest. 2021;131(20):e145035. https://doi.org/10.1172/JCI145035.
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Research Article Oncology

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

Abstract

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.

Authors

Shini Liu, Qiong Zou, Jie-Ping Chen, Xiaosai Yao, Peiyong Guan, Weiting Liang, Peng Deng, Xiaowei Lai, Jiaxin Yin, Jinghong Chen, Rui Chen, Zhaoliang Yu, Rong Xiao, Yichen Sun, Jing Han Hong, Hui Liu, Huaiwu Lu, Jianfeng Chen, Jin-Xin Bei, Joanna Koh, Jason Yongsheng Chan, Baohua Wang, Tiebang Kang, Qiang Yu, Bin-Tean Teh, Jihong Liu, Ying Xiong, Jing Tan

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Figure 3

Enhancer reprogramming accompanies acquired resistance to MEK inhibitors.

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Enhancer reprogramming accompanies acquired resistance to MEK inhibitors...
(A) Genomic distribution of H3K27ac, H3K4me1, and H3K4me3 peaks in A2780-P and A2780-R cells. (B) Plot of the average level of H3K27ac, H3K4me1, and H3K4me3 peaks centered at the TSS in A2780-P or A2780-R cells. (C) Venn diagram showing the number and overlaps of enhancers and promoters between A2780-P and A2780-R cells overlapped by MAnorm (https://github.com/shao-lab/MAnorm). Common peaks merged. (D and E) Distribution of histone markers surrounding the summit of H3K27ac peaks, in gained or lost enhancer regions (D) and promoter regions (E). Black borders, A2780-P; dark red borders, A2780-R. Only one of the duplicates was plotted, as consistent results were observed in the other replicate. Each row represents 1 peak centered at the midpoint between two 2-kb flanking regions. (F) Scatterplot of the correlation between H3K27ac mark intensity and fold change of corresponding gene expressions. The horizontal axis illustrates the differences between resistant and parental cell lines, measured in counts per million mapped reads (CPM). Only genes of at least 4-fold change and H3K27ac changes of 500 CPM are shown. (G) Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis enriched by downregulated genes in A2780-R (relative to A2780-P) showed that the MAPK pathway was significantly enriched. NES, normalized enrichment score. (H) Relative mRNA levels of ERK transcriptional targets in A2780-P/R cells (left) and OVCAR5-P/R cells (right). Results are represented as mean ± SD of 3 independent experiments. *P < 0.05, **P < 0.01, ***P < 0.001 by unpaired Student’s t test. (I) ChIP-Seq profiles show the ChIP-Seq signal (y axis, reads per million) for H3K27ac, H3K4me1, and H3K4me3 at genomic loci of DUSP6, ETV4, and SPRY4. (J) The results showed relative mRNA level of DUSP6 in 9 commercial cell lines and 7 patient-derived cells. Results are represented as mean ± SD of 4 independent experiments.