JAK inhibition results in aggressive cutaneous squamous cell carcinoma through MAPK pathway activation and shapes the tumor immune microenvironment to create novel therapeutic opportunities [RNA-seq]

Secondary malignancies are the most feared adverse effects of cancer therapies. In this study, we explore the oncogenic effects of the JAK inhibitor ruxolitinib on the skin. First, we demonstrate an epidemiological association between ruxolitinib exposure and development of aggressive cutaneous squamous cell carcinoma (cSCC), by conducting a disproportionality analysis on international pharmacovigilance data and a large local cohort study. We next demonstrate the causal link between ruxolitinib treatment and cSCC development, using in vitro and in vivo models. Mechanistically, we reveal that ruxolitinib induces transformation of pre-malignant keratinocytes into aggressive cSCC by activating the MAPK pathway through the COT kinase. Intriguingly, ruxolitinib also reshapes the immune microenvironment of cSCC resulting in T regulatory cells reduction and T CD8+ cells increase. Ruxolitinib-mediated immune microenvironment effects create new therapeutic opportunities by enhancing anti-PD1 treatment efficacy in cSCC and other immunotherapy resistant cancer types such as pancreatic cancer and acute myeloid leukemia.