MCC is a highly aggressive primary cutaneous neuroendocrine carcinoma that typically occurs in elderly and immunocompromised individuals, often presenting in sun-exposed areas such as the extremities, head, and neck region. MCC has a recurrence rate of around 40% after definitive therapy, significantly higher than that of other skin cancers like invasive melanoma (approximately 19%), squamous cell carcinoma (approximately 5%-9%), or basal cell carcinoma (approximately 1%-2%) [31]. Tumors located in the head and neck region pose challenges for surgical treatment, while chemotherapies and immunotherapies have limitations due to toxic side effects. This underscores the importance of investigating the molecular mechanisms underlying MCC pathogenesis to identify tumor-targeted treatments directed against specific pathogenic factors.
Selinexor was first proposed as a targeted MCC therapy by Gupta et al. after discovering decreased expression of XPO1, LT, and sT antigens in MCCP cell lines [32]. XPO1 is frequently overexpressed in human cancers and functions as an oncogenic driver [33]. By preventing the transport of oncogenic mRNA out of the nucleus, XPO1-inhibitors such as selinexor represent an attractive anti-cancer therapy. Further studies have uncovered selinexor’s inhibitory effects on the DNA damage response pathway, fatty acid synthesis pathway, and downregulation of critical biomarkers of MCC carcinogenesis [18, 17, 27].
The prostaglandin synthesis pathway investigated in this study represents a promising avenue for targeted MCC therapy. COX-2 expression is detected in 77% of primary MCC tumors, and its well-documented overexpression has been shown to promote tumorigenesis [28, 30]. Both COX-1 and COX-2 enzymes are responsible for converting arachidonic acids into prostaglandin H2 (PGH2), which serves as a precursor for various prostaglandins (PGD2, PGE2, PGF2, PGI2) and thromboxane A2 (TXA2) (Fig. 3). TXA2 binds to its downstream receptor TXA2R. PGE2 binds to downstream E prostanoid (EP) receptors (EP1, EP2, EP3, EP4), while PGD2, PGF2, and PGI2 bind to their respective downstream receptors (PTGDR, PTGFR, PTGIR). Overexpression of EP receptors has been linked to tumor growth promotion, tumor-associated angiogenesis, regulation of cellular migration, and has been identified in various malignancies [29, 34, 35, 36, 37, 38]. Notably, EP-receptor targeted therapies are being investigated for colorectal and breast cancer [39, 40].
Our study demonstrates that selinexor treatment of MCCP cell lines results in highly significant dose-dependent reductions in the expression of COX enzymes, prostaglandin synthases (PGE2S), and downstream receptors (EP, PTGIR, PTGDR) in vitro. These findings underscore the potential of selinexor as a promising therapeutic agent. Furthermore, our study provides insights into yet other mechanisms by which selinexor may inhibit carcinogenic pathways, potentially by inhibiting exportin transporters and impeding the relocation of MCPyV virally encoded tumor antigens to the cytoplasm, thus curtailing the dysregulation of downstream pathways.
Selinexor exhibits a dose-dependent reduction of key mediators in the prostaglandin synthesis pathway in MCCP cell lines. This pathway has been implicated in carcinogenesis and found to be dysregulated in primary MCC tumors. Our findings provide further insights into the mechanism of action and efficacy of selinexor in vitro, suggesting its potential involvement in inhibiting the prostaglandin synthesis pathway in cancer cells. Further studies are needed to investigate whether MCCN displays a similar prostaglandin pathway dysregulation, and if selinexor maintains its effect in MCCN.
Selinexor is used in the second-line setting for patients with multiple myeloma [15]. Frequently reported adverse effects include gastrointestinal, constitutional, and hematologic (thrombocytopenia and neutropenia). These adverse effects are reversible and can be managed with supportive care. Importantly, no reports or evidence of major organ or cumulative toxicities after long-term treatment have been found [41, 42]. The low side-effect profile coupled with our studies may allow for expanded indications of selinexor for MCC.
Selinexor offers a promising novel therapeutic option for patients with aggressive metastatic MCC who demonstrate inadequate response to chemotherapy and immunotherapy or experience significant toxic side effects. It may be used as a standalone treatment or in combination with existing treatment options. Additional research and clinical studies are necessary to assess the impact of selinexor through in vivo experiments and its efficacy in patients with MCC. Moreover, our findings prompt the exploration of the potential therapeutic role of COX-inhibitors in the treatment of MCC.