JAK1/2 inhibition promotes aggressive cutaneous carcinogenesis through COT kinase-mediated alternative MAPK pathway activation.
13 affiliations
- 1INSERM UMR 1342, Institut de Recherche Saint-Louis, Paris, France.
- 2Université Paris Cité, INSERM Clinical Investigation Center (CIC) 1427, AP-HP, Hôpital Saint-Louis, Paris, France.
- 3Quantitative Biosciences Institute and
- 4Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, California, USA.
- 5Service de Pathologie, INSERM U976, Institut de Recherche Saint-Louis, and
- 6Dermato-oncology Unit and CIC, Cancer Institute AP-HP.Nord Paris Cité, INSERM U976, Université Paris Cité, AP-HP, Hôpital Saint-Louis, Paris, France.
- 7Université de Bordeaux, INSERM, BPH, U1219, AHeaD Team, CHU de Bordeaux, Pôle de Santé Publique, Service de Pharmacologie Médicale, Bordeaux, France.
- 8Service de Génomique des Tumeurs et Pharmacologie and
- 9Service de Biostatistiques, Université Paris Cité, AP-HP, Hôpital Saint-Louis, Paris, France.
- 10Université Paris Sciences et Lettres, Institut Curie, CurieCoreTech Spectrométrie de Masse Protéomique, Paris, France.
- 11Université Côte d’Azur, INSERM U1065 (C3M), Microenvironment, Signaling and Cancer, Nice, France.
- 12Département d’Hématologie et d’Immunologie and
- 13Laboratoire de Biologie Cellulaire, Université Paris Cité, AP-HP, Hôpital Saint-Louis, Paris, France.
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.
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BibTeX
@article{pasquer2026jak12,
title = {{JAK1/2 inhibition promotes aggressive cutaneous carcinogenesis through COT kinase-mediated alternative MAPK pathway activation.}},
author = {Hélène Pasquer and Antoine Forget and Maxime Battistella and Raphael Marie and Léa Provent and Barouyr Baroudjian and Emmanuelle Latour and Cécile Culeux and Blandine Roux and Khansa Saadallah and Amandine Gouverneur and Maxime Demourgues and Fanélie Jouenne and Jérôme Lambert and Bérangère Lombard and Damarys Loew and Sophie Tartare-Deckert and Lionel Adès and Emmanuel Raffoux and Bruno Cassinat and Juliette Soret-Dulphy and Pernelle Noize and Samia Mourah and Camille Lobry and Jean-Jacques Kiladjian and Alexandre Puissant and Céleste Lebbé and Lina Benajiba},
journal = {The Journal of clinical investigation},
year = {2026},
month = nov,
doi = {10.1172/jci199141},
url = {https://europepmc.org/article/MED/42969233},
note = {CC BY},
}
RIS
TY - JOUR
TI - JAK1/2 inhibition promotes aggressive cutaneous carcinogenesis through COT kinase-mediated alternative MAPK pathway activation.
AU - Hélène Pasquer
AU - Antoine Forget
AU - Maxime Battistella
AU - Raphael Marie
AU - Léa Provent
AU - Barouyr Baroudjian
AU - Emmanuelle Latour
AU - Cécile Culeux
AU - Blandine Roux
AU - Khansa Saadallah
AU - Amandine Gouverneur
AU - Maxime Demourgues
AU - Fanélie Jouenne
AU - Jérôme Lambert
AU - Bérangère Lombard
AU - Damarys Loew
AU - Sophie Tartare-Deckert
AU - Lionel Adès
AU - Emmanuel Raffoux
AU - Bruno Cassinat
AU - Juliette Soret-Dulphy
AU - Pernelle Noize
AU - Samia Mourah
AU - Camille Lobry
AU - Jean-Jacques Kiladjian
AU - Alexandre Puissant
AU - Céleste Lebbé
AU - Lina Benajiba
PY - 2026
DA - 2026/11/02
JO - The Journal of clinical investigation
DO - 10.1172/jci199141
UR - https://europepmc.org/article/MED/42969233
AB - 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.
SN - 0021-9738
SN - 1558-8238
ER -