Inhibition of the ATR-CHK1 signaling pathway sensitizes MCPyV-positive Merkel cell carcinoma to gemcitabine
- 1Department of Molecular, Cellular, and Biomedical Sciences, University of New Hampshire
Abstract
Merkel cell carcinoma (MCC) is the primary cutaneous neuroendocrine carcinoma with a mortality rate higher than that of melanoma and other common skin cancers. In the United States, most cases of MCC are positive for Merkel cell polyomavirus (MCPyV), in which the viral small T antigen (ST) recruits the Tip60-EP400 chromatin remodeling complex to L-Myc, a MYC family protein with oncogenic properties. This complex initiates MYC-dependent transcriptional programs that induce replication stress. Given that ATR-CHK1 is crucial for responding to replication stress and maintaining genomic integrity, we investigated whether this ST-driven L-Myc/Tip60-EP400 program is associated with heightened reliance on ATR-CHK1 signaling in MCPyV+ MCC. Here, we demonstrate that MCPyV+ MCC cells exhibit a pronounced dependency on the ATR-CHK1 pathway and that combining CHK1 inhibition with the replication-blocking chemotherapeutic agent gemcitabine produces synergistic antiproliferative effects. In MCPyV+ MCC cell lines, the gemcitabine-CHK1 inhibitor combination markedly reduced cell viability and increased DNA damage and apoptosis compared to either agent alone. Conversely, in MCPyV− cell lines, combination responses and apoptotic induction were attenuated, although some sensitivity to CHK1 inhibition alone was observed. These findings support ATR-CHK1 signaling as a candidate therapeutic vulnerability in MCPyV+ MCC and provide a rationale for further preclinical and translational evaluation of ATR or CHK1 inhibitors in combination with gemcitabine in this virally driven cancer.
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BibTeX
@article{proctor2026inhibition,
title = {{Inhibition of the ATR-CHK1 signaling pathway sensitizes MCPyV-positive Merkel cell carcinoma to gemcitabine}},
author = {Evelyn V. Proctor and Sherine F. Elsawa and Sarah R. Walker and Jingwei Cheng},
journal = {BMC Cancer},
year = {2026},
month = jul,
doi = {10.1186/s12885-026-16505-1},
url = {https://doi.org/10.1186/s12885-026-16505-1},
note = {CC BY},
}
RIS
TY - JOUR
TI - Inhibition of the ATR-CHK1 signaling pathway sensitizes MCPyV-positive Merkel cell carcinoma to gemcitabine
AU - Evelyn V. Proctor
AU - Sherine F. Elsawa
AU - Sarah R. Walker
AU - Jingwei Cheng
PY - 2026
DA - 2026/07/01
JO - BMC Cancer
DO - 10.1186/s12885-026-16505-1
UR - https://doi.org/10.1186/s12885-026-16505-1
AB - Merkel cell carcinoma (MCC) is the primary cutaneous neuroendocrine carcinoma with a mortality rate higher than that of melanoma and other common skin cancers. In the United States, most cases of MCC are positive for Merkel cell polyomavirus (MCPyV), in which the viral small T antigen (ST) recruits the Tip60-EP400 chromatin remodeling complex to L-Myc, a MYC family protein with oncogenic properties. This complex initiates MYC-dependent transcriptional programs that induce replication stress. Given that ATR-CHK1 is crucial for responding to replication stress and maintaining genomic integrity, we investigated whether this ST-driven L-Myc/Tip60-EP400 program is associated with heightened reliance on ATR-CHK1 signaling in MCPyV+ MCC. Here, we demonstrate that MCPyV+ MCC cells exhibit a pronounced dependency on the ATR-CHK1 pathway and that combining CHK1 inhibition with the replication-blocking chemotherapeutic agent gemcitabine produces synergistic antiproliferative effects. In MCPyV+ MCC cell lines, the gemcitabine-CHK1 inhibitor combination markedly reduced cell viability and increased DNA damage and apoptosis compared to either agent alone. Conversely, in MCPyV− cell lines, combination responses and apoptotic induction were attenuated, although some sensitivity to CHK1 inhibition alone was observed. These findings support ATR-CHK1 signaling as a candidate therapeutic vulnerability in MCPyV+ MCC and provide a rationale for further preclinical and translational evaluation of ATR or CHK1 inhibitors in combination with gemcitabine in this virally driven cancer.
SN - 1471-2407
ER -