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Selinexor is a novel inhibitor of DNA damage response in Merkel cell carcinoma
Stephen Andrew Moore1,2, Deepika Narayanan1, Rebecca A Simonette1
1Department of Dermatology, The University of Texas McGovern Medical School, Houston, TX, USA.
Abstract:
Merkel cell carcinoma (MCC) is a highly lethal cutaneous carcinoma, which in ~80% of cases in the USA is aetiologically linked to Merkel cell polyomavirus (MCPyV). Immune checkpoint inhibitors (ICIs) can successfully treat ~50% of patients with metastatic MCC, but some MCCs are refractory to ICIs, possibly due to altered DNA damage response (DDR). Selinexor, an anticancer therapy that is currently approved in combination with chemotherapy for multiple myeloma, downregulates the small T and large T tumour antigens in MCC through selective inhibition of nuclear exportin 1 (XPO1). We examined the effect of varying doses of selinexor on DDR protein expression in MCPyV-positive and MCPyV-negative MCC cells. Selinexor was found to inhibit DDR protein expression in both MCPyV-positive and MCPyV-negative cells. Addition of selinexor alone or combined with ICI may be a promising treatment for MCC, but further in vivo research and clinical trials are required to validate these findings.
Insights
Selinexor, an anticancer drug, inhibits DNA damage response (DDR) proteins in Merkel cell carcinoma (MCC) cells, regardless of Merkel cell polyomavirus (MCPyV) status. This suggests selinexor combined with immune checkpoint inhibitors (ICIs) could be a promising MCC treatment.
Area of Science:
- Oncology
- Cancer Biology
- Virology
Background:
- Merkel cell carcinoma (MCC) is an aggressive skin cancer linked to Merkel cell polyomavirus (MCPyV).
- Immune checkpoint inhibitors (ICIs) show efficacy in metastatic MCC, but resistance occurs, potentially due to DNA damage response (DDR) alterations.
- Selinexor targets nuclear exportin 1 (XPO1) to downregulate MCC tumor antigens.
Purpose of the Study:
- To investigate the effect of selinexor on DDR protein expression in MCPyV-positive and MCPyV-negative MCC cells.
- To evaluate selinexor's potential as a therapeutic agent for MCC, alone or in combination with ICIs.
Main Methods:
- Treatment of MCPyV-positive and MCPyV-negative MCC cell lines with varying doses of selinexor.
- Analysis of DDR protein expression following selinexor treatment.
Main Results:
- Selinexor effectively inhibited DDR protein expression in both MCPyV-positive and MCPyV-negative MCC cells.
- The drug demonstrated a dose-dependent effect on DDR inhibition.
Conclusions:
- Selinexor impacts DDR pathways in MCC, irrespective of MCPyV infection.
- Combination therapy with selinexor and ICIs warrants further investigation in preclinical models and clinical trials for MCC treatment.
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