Related Experiment Video
Updated: Oct 22, 2025
Testing Targeted Therapies in Cancer using Structural DNA Alteration Analysis and Patient-Derived Xenografts
Published on: July 25, 2020
Targeting enhancer reprogramming to mitigate MEK inhibitor resistance in preclinical models of advanced ovarian
Shini Liu1, Qiong Zou1, Jie-Ping Chen1
1Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, China.
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.
Insights
Targeting the MAPK pathway in ovarian cancer shows promise, but drug resistance is a challenge. Combining HDAC inhibitors with trametinib overcomes resistance by reversing enhancer reprogramming, offering a synergistic antitumor effect.
Area of Science:
- Oncology
- Epigenetics
- Molecular Biology
Background:
- Ovarian cancer exhibits aberrant mitogen-activated protein kinase (MAPK) pathway activation.
- Targeting the MAPK pathway is a key therapeutic strategy, but drug resistance limits clinical efficacy.
- Understanding resistance mechanisms is crucial for improving ovarian cancer treatment.
Purpose of the Study:
- To investigate the mechanisms of acquired resistance to MEK inhibitors in ovarian cancer.
- To identify potential strategies to overcome MEK inhibitor resistance.
- To evaluate the therapeutic potential of combining epigenetic therapy with MAPK pathway inhibitors.
Main Methods:
- Established patient-derived ovarian cancer models resistant to MEK inhibitors.
- Analyzed enhancer reprogramming and its role in MAPK pathway regulation.
- Conducted epigenetic compound screening to identify modulators of enhancer activity.
- Evaluated the synergistic antitumor effects of combined HDAC inhibitor and trametinib treatment in vitro and in vivo.
Main Results:
- Trametinib resistance was associated with enhancer reprogramming and decreased expression of MAPK pathway negative regulators.
- Enhancer decommissioning led to constitutive ERK activation, causing acquired resistance.
- HDAC inhibitors reversed enhancer reprogramming and restored sensitivity to trametinib.
- Combination therapy demonstrated synergistic antitumor effects in preclinical models.
Conclusions:
- Enhancer reprogramming is a potential mechanism driving MAPK inhibitor resistance in ovarian cancer.
- Targeting epigenetic pathways concurrently with MAPK signaling offers a promising strategy for treating advanced ovarian cancer.
- Combination of HDAC inhibitors and trametinib shows significant therapeutic potential.
Related Concept Videos
02:57Targeted Cancer Therapies
There are several types of targeted therapies against...
01:16In-vitro Mutagenesis