Ruxolitinib inhibits cyclosporine-induced proliferation of cutaneous squamous cell carcinoma

Abstract

Organ transplant recipients (OTRs) on cyclosporine A (CSA) are prone to catastrophic cutaneous squamous cell carcinoma (SCC). Allograft-sparing, cancer-targeting systemic treatments are unavailable. We have shown increased risk for catastrophic SCC in OTRs via CSA-mediated induction of IL-22. Herein, we found that CSA drives SCC proliferation and tumor growth through IL-22 and JAK/STAT pathway induction. We in turn inhibited SCC growth with an FDA-approved JAK1/2 inhibitor, ruxolitinib. In human SCC cells, the greatest proliferative response to IL-22 and CSA treatment occurred in nonmetastasizing lines. IL-22 treatment upregulated JAK1 and STAT1/3 in A431 SCC cells. JAK/STAT pathway genes were highly expressed in tumors from a cohort of CSA-exposed OTRs and in SCC with high risk for metastasis. Compared with immunocompetent SCC, genes associated with innate immunity, response to DNA damage, and p53 regulation were differentially expressed in SCC from OTRs. In nude mice engrafted with human A431 cells, IL-22 and CSA treatment increased tumor growth and upregulated IL-22 receptor, JAK1, and STAT1/3 expression. Ruxolitinib treatment significantly reduced tumor volume and reversed the accelerated tumor growth. CSA and IL-22 exacerbate aggressive behavior in SCC. Targeting the IL-22 axis via selective JAK/STAT inhibition may reduce the progression of aggressive SCC in OTRs, without compromising immunosuppression.

Cutaneous Squamous Cell Carcinoma: From Biology to Therapy

“…Using ruxolitinib, an FDA-approved JAK1/2 inhibitor, in human CSCC cells and xenografts reduces proliferation and growth. This could be a feasible option for preventing CSCC in OTRs who face long-term immunosuppression [154].…”

A Unique Panel of Patient-Derived Cutaneous Squamous Cell Carcinoma Cell Lines Provides a Preclinical Pathway for Therapeutic Testing

“…C-MYC-dependent pro-apoptotic protein NOXA upregulation confers inhibitor susceptibility for rapid BAK-dependent death. [68]T1, T8, MET1, MET4Early stage T1 demonstrates the greatest proliferative response to IL-22 treatment. cSCC proliferation was inhibited by JAK1/2 inhibitor ruxolitinib in vitro with tumour size reduction in vivo; however, this was demonstrated in the A431 cSCC epidermoid carcinoma line only and not in T1, T8, MET1 or MET4 lines.…”

Aggressive cutaneous squamous cell carcinoma in a hydroxyurea‐ and ruxolitinib‐pretreated patient with polycythaemia vera

“…An increased occurrence of non‐melanoma skin cancer (NMSC), such as cutaneous squamous cell carcinoma (cSCC), has not only been described following the long‐term treatment with the anti‐metabolite hydroxyurea (HU) but also under Janus kinase 1 and 2 inhibitors (JAKi) therapy for haematological malignancies. It has been reported that NMSC developing in patients on ruxolitinib therapy exhibit a more aggressive and metastatic profile 1–6 . We report a polycythaemia vera (PV) and long‐term HU and ruxolitinib therapy who developed highly aggressive cSCC not responding to cetuximab and pembrolizumab treatment.…”