# Transcriptional Profiling Reveals Lineage-Specific Characteristics in ATR/CHK1 Inhibitor-Resistant Endometrial Cancer

## TL;DR

This study identifies how endometrial cancer cells develop resistance to ATR/CHK1 inhibitors and reveals distinct gene patterns linked to resistance based on cancer type and drug used.

## Contribution

The study establishes isogenic resistant cell models and identifies lineage-specific transcriptomic profiles of resistance to ATR/CHK1 inhibitors in endometrial cancer.

## Key findings

- MSI-h resistant clones show enrichment in epithelial-mesenchymal transition and interferon responses.
- CNH-derived resistant clones exhibit divergent transcriptomic patterns depending on the inhibitor class.
- THBS1, EDN1, and TENM2 are consistently upregulated in all resistant models.

## 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.