Related Experiment Video
Updated: Jan 29, 2026
Sentinel Lymph Node Mapping and Biopsy for Endometrial Cancer at Early Stage with Laparoscopy
Published on: August 19, 2021
Transcriptional Profiling Reveals Lineage-Specific Characteristics in ATR/CHK1 Inhibitor-Resistant Endometrial Cancer
Tzu-Ting Huang1, Jung-Min Lee1
1Women's Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Abstract:
Recurrent endometrial cancer (EC) has limited therapeutic options beyond platinum-based chemotherapy, highlighting the need to identify exploitable molecular vulnerabilities. Tumors with high genomic instability, including microsatellite instability-high (MSI-h) or copy-number-high (CNH) ECs, rely on the ATR-CHK1 signaling pathway to tolerate replication stress and maintain genome integrity, making this pathway an attractive therapeutic target. However, acquired resistance to ATR and CHK1 inhibitors (ATRi/CHK1i) often develops, and the transcriptomic basis of this resistance in EC remains unknown. Here, we established isogenic ATRi- and CHK1i-resistant cell line models from MSI-h (HEC1A) and CNH (ARK2) EC lineages and performed baseline transcriptomic profiling to characterize stable resistance-associated states. MSI-h-derived resistant clones adopted a unified transcriptional state enriched for epithelial-mesenchymal transition, cytokine signaling, and interferon responses, while ATRi-resistant models showing additional enrichment of developmental and KRAS/Notch-associated pathways. In contrast, CNH-derived resistant clones diverged by inhibitor class, with ATRi resistance preferentially enriching proliferation-associated pathways and CHK1i resistance inducing interferon signaling. Notably, THBS1, EDN1, and TENM2 were consistently upregulated across all resistant models relative to parental lines. Together, these findings demonstrate that acquired resistance to ATRi and CHK1i in EC is shaped by both lineage and inhibitor class and provide a transcriptomic framework that may inform future biomarker development and therapeutic strategies.
Insights
Acquired resistance to ATR/CHK1 inhibitors in endometrial cancer (EC) is linked to specific gene expression changes. Understanding these transcriptomic shifts in microsatellite instability-high and copy-number-high ECs can guide future therapies.
Area of Science:
- Oncology
- Molecular Biology
- Genomics
Background:
- Recurrent endometrial cancer (EC) has limited treatment options, necessitating novel therapeutic strategies.
- The ATR-CHK1 signaling pathway is a key target in high-risk EC due to its role in maintaining genome integrity.
- Acquired resistance to ATR and CHK1 inhibitors (ATRi/CHK1i) is a significant clinical challenge, with its transcriptomic basis in EC being largely unknown.
Purpose of the Study:
- To investigate the transcriptomic changes associated with acquired resistance to ATRi/CHK1i in different EC subtypes.
- To identify common and distinct molecular mechanisms driving resistance in microsatellite instability-high (MSI-h) and copy-number-high (CNH) EC models.
- To establish a transcriptomic framework for understanding and potentially overcoming resistance to ATRi/CHK1i in EC.
Main Methods:
- Development of isogenic ATRi- and CHK1i-resistant cell line models from MSI-h (HEC1A) and CNH (ARK2) EC lineages.
- Comprehensive transcriptomic profiling of resistant cell lines and their parental counterparts.
- Bioinformatic analysis to identify differentially expressed genes and enriched pathways in resistance states.
Main Results:
- MSI-h derived resistant clones exhibited a unified transcriptional state characterized by epithelial-mesenchymal transition, cytokine signaling, and interferon responses.
- ATRi-resistant MSI-h models additionally showed enrichment of developmental and KRAS/Notch-associated pathways.
- CNH-derived resistant clones displayed divergent transcriptomic profiles based on inhibitor class: ATRi resistance enriched proliferation pathways, while CHK1i resistance induced interferon signaling.
- Genes including *THBS1*, *EDN1*, and *TENM2* were consistently upregulated across all resistant models.
Conclusions:
- Acquired resistance to ATRi and CHK1i in EC is influenced by both the cancer's genetic lineage (MSI-h vs. CNH) and the specific inhibitor used.
- Distinct transcriptomic states are associated with resistance, offering potential targets for overcoming therapeutic limitations.
- These findings provide a molecular basis for developing biomarkers and novel therapeutic strategies for recurrent EC.
Related Concept Videos
01:52Eukaryotic Transcription Inhibitors
Eukaryotic transcription inhibitors usually contain two distinct domains, a...
02:56Treatment Resistant Cancers
02:16Transcription Factors
02:42Eukaryotic Transcription Activators
The binding domains are capable of recognizing and interacting with regulatory sequences on the DNA. These...
01:10Transcription
Transcription is the process of synthesizing RNA from a DNA sequence by RNA polymerase. It is the first step in producing a protein from a gene sequence. Additionally, many other proteins and regulatory sequences are involved in the proper synthesis of messenger RNA (mRNA). Regulation of transcription is responsible for the differentiation of all the different types of cells and often for the proper cellular response to environmental signals.
Transcription Can Produce Different Kinds...
02:23Master Transcription Regulators