Related Experiment Video
Updated: Jan 29, 2026
05:52
Sentinel Lymph Node Mapping and Biopsy for Endometrial Cancer at Early Stage with Laparoscopy
Published on: August 19, 2021
13.2K
Transcriptional Profiling Reveals Lineage-Specific Characteristics in ATR/CHK1 Inhibitor-Resistant Endometrial
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.
Biomolecules
|January 28, 2026
Summary
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
11.0K
Certain biochemical processes, such as embryonic development and cell growth regulation, depend on the repression of specific genes. DNA binding proteins known as eukaryotic transcription inhibitors regulate the repression of gene expression in eukaryotes. The presence of these inhibitors at the required location and time in the cell is triggered by the presence of hormones and additional signals from other cells.
Eukaryotic transcription inhibitors usually contain two distinct domains, a...
Eukaryotic transcription inhibitors usually contain two distinct domains, a...
11.0K
02:56Treatment Resistant Cancers
3.7K
Cancer is the second leading cause of death in the United States. A cancer cell is genetically unstable and hence can mutate faster. They can also modify their microenvironment and escape immune surveillance. The difficulties in treating cancer are further compounded by the emergence of rapid resistance to anticancer drugs. The most common ways to attain resistance in cancer cells include alteration in drug transport and metabolism, modification of drug target, elevated DNA damage response, or...
3.7K
02:16Transcription Factors
82.7K
Tissue-specific transcription factors contribute to diverse cellular functions in mammals. For example, the gene for beta globin, a major component of hemoglobin, is present in all cells of the body. However, it is only expressed in red blood cells because the transcription factors that can bind to the promoter sequences of the beta globin gene are only expressed in these cells. Tissue-specific transcription factors also ensure that mutations in these factors may impair only the function of...
82.7K
02:42Eukaryotic Transcription Activators
12.8K
Transcription activators are proteins that promote the transcription of genes from DNA to RNA. In most cases, these proteins contain two separate domains ‒ a domain that binds to DNA and a domain for activating transcription; however, in some cases, a single domain is responsible for both binding and activation of transcription, as seen in the glucocorticoid receptor and MyoD.
The binding domains are capable of recognizing and interacting with regulatory sequences on the DNA. These...
The binding domains are capable of recognizing and interacting with regulatory sequences on the DNA. These...
12.8K
01:10Transcription
156.1K
Overview
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...
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...
156.1K
02:23Master Transcription Regulators
7.8K
Master transcription regulators are regulatory proteins that are predominantly responsible for regulating the expression of multiple genes. Often these genes work in concert to drive a complex process. Activation of a master transcription regulator can lead to a cascade of transcriptional activation necessary for that outcome. These regulators can directly bind to the regulatory sequences of the various genes involved, or they can indirectly regulate transcription by binding to regulatory...
7.8K