198 The JAK1/2 inhibitor ruxolitinib induces cell cycle arrest and apoptosis through inhibiting STAT3 phosphorylation in squamous cell carcinoma

Abstract

Ruxolitinib is an FDA approved JAK1/2 inhibitor that has shown efficacy in human head and neck squamous cell carcinoma, lung, and breast carcinoma, however, its therapeutic effect has not been elucidated in cutaneous squamous cell carcinoma (cSCC). cSCC is the second most common form of skin cancer, which causes significant morbidity due to local recurrence and metastasis. Therefore, there is an unmet need for novel therapeutic approaches for this malignancy. Here, we investigated whether inhibition of the JAK/STAT pathway has antitumor effects in cSCC. We found that JAK1/2 inhibition with ruxolitinib in the human SCC39 cell line in vitro resulted in STAT3 signaling-dependent decreased proliferation and cell cycle arrest at G2/M. This response was accompanied by decreased levels of cyclin D1 and increased levels p27Kip1. Moreover, ruxolitinib induced apoptosis in SCC cells as demonstrated by increased levels of cleaved caspase-3. Furthermore, we found that in vivo, topical application of ruxolitinib inhibited a TPA-induced increase in keratinocyte proliferation and a subsequent increase in epidermal thickness in Balb/c mice. In this model of cSCC tumor promotion, we also found that topical JAK inhibition resulted in a marked inflammatory infiltrate in TPA-treated animals. Taken together, we demonstrated the therapeutic potential of JAK1/2/STAT3 inhibition in cSCC, making ruxolitinib a promising anti-cancer drug against SCC development and progression. Moreover, this treatment option will be beneficial for high-risk groups such as solid organ transplant recipients or patients with recessive dystrophic epidermolysis bullosa where aggressive cSCC is a major complication resulting in considerable morbidity and mortality.