JAK1/2 inhibition promotes aggressive cutaneous carcinogenesis through COT kinase-mediated alternative MAPK pathway activation
In brief
Ruxolitinib links to aggressive skin cancers through an alternate growth pathway
International safety data and a large cohort linked ruxolitinib use to aggressive skin squamous cell cancer, while laboratory and animal models showed the drug can drive cancerous changes in skin cells. The researchers traced this effect mainly to COT-driven MAPK signaling and also found evidence of increased melanoma risk, but the size of the clinical risks remains unclear.
- Journal
- The Journal of clinical investigation (Q1)
- Published
- 2 November 2026
- Study design
- Cohort / observational study
- Evidence level
- Level 3, Low (CEBM 3b)
- Authors
- Hélène Pasquer, Antoine Forget, Maxime Battistella, Raphael Marie, Léa Provent, Barouyr Baroudjian, et al.
- PMID
- 42969233
- DOI
- 10.1172/JCI199141
Why clinicians should know about it
- Picked for Dermatology (paper of the day, 5 November 2026): Cutaneous SCC and melanoma risk with JAK inhibition
Abstract
Secondary malignancies are the most feared adverse effects of cancer therapies. In this study, we explored the cutaneous oncogenic effects of the JAK inhibitor ruxolitinib. First, we demonstrated an epidemiological association between ruxolitinib exposure and development of aggressive cutaneous squamous cell carcinoma (cSCC) by analyzing international pharmacovigilance data and conducting a large cohort study. We next demonstrated the causal link between ruxolitinib treatment and cSCC development using in vitro and in vivo models. Mechanistically, we revealed that ruxolitinib induces transformation of premalignant keratinocytes by activating the MAPK pathway. This effect is mostly driven by JAK2 inhibition, suggesting a pharmacological class effect. To unravel the mechanistic underpinnings of ruxolitinib-induced MAPK activation, we then applied a phosphoproteomic approach. Alternative MAPK signaling downstream of the kinase COT was pinpointed as the main activator of the pathway in this context. The central role of COT was functionally validated using chemical inhibition, genetic impairment, and inactivated COT mutant expression. Indeed, impairment of COT rescued the pro-oncogenic effect of ruxolitinib. Finally, we determined using a combination of epidemiological, in vitro, and in vivo studies that ruxolitinib-mediated oncogenic effects also result in an increased risk of melanoma, suggesting that the uncovered cellular signaling mechanism might be extrapolated to other cancers with a high dependency on the MAPK pathway.
Abstract as published, via PubMed.
For healthcare professionals. The summary is generated by AI from the published abstract, and the evidence level is assigned automatically from the study design on the Oxford CEBM hierarchy. Neither is medical advice. Read the full paper before changing practice.