JAK-STAT Pathway Inhibitors: A New Jackpot for Dermatology
Abstract
Dermatology is experiencing an explosion of new therapies targeting the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway. This pathway plays a critical role in regulating immune cells, especially the polarization of T helper cells via cytokine receptors. Already, a number of dermatologic therapies target the extracellular environment, decreasing the levels of free inflammatory cytokines such as interleukin (IL)-17, IL-23, and tumour necrosis factor alpha (TNFα), or inhibiting cytokine receptors such as IL-17 receptors or IL-4 receptors. Such therapies are usually delivered as large antibody-like molecules called biologics and need to be given by injection. The new therapies, in the form of small molecules that inhibit intracellular kinases, can be given orally or topically. They are called JAK inhibitors (JAKi). For several years, they have found use in rheumatology (tofacitinib), hematologic oncology (ruxolitinib), veterinary medicine (oclacitinib) and basic science research. They are gaining increasing traction in dermatology.
References
Seif F, Khoshmirsafa M, Aazami H, Mohsenzadegan M, Sedighi G, Bahar M. The role of JAK-STAT signaling pathway and its regulators in the fate of T helper cells. Cell Commun Signal. 2017;15(1):23.
Morris R, Kershaw NJ, Babon JJ. The molecular details of cytokine signaling via the JAK/STAT pathway. Protein Sci. 2018;27(12):1984-2009.
Krolewski JJ, Lee R, Eddy R, Shows TB, Dalla-Favera R. Identification and chromosomal mapping of new human tyrosine kinase genes. Oncogene. 1990;5(3):277-82.
Wilks AF, Harpur AG, Kurban RR, Ralph SJ, Zürcher G, Ziemiecki A. Two novel protein-tyrosine kinases, each with a second phosphotransferase-related catalytic domain, define a new class of protein kinase. Mol Cell Biol. 1991;11(4):2057-65.
Babon JJ, Lucet IS, Murphy JM, Nicola NA, Varghese LN. The molecular regulation of Janus kinase (JAK) activation. Biochem J. 2014;462(1):1-13.
Miyazaki T, Kawahara A, Fujii H, Nakagawa Y, Minami Y, Liu ZJ, et al. Functional activation of Jak1 and Jak3 by selective association with IL-2 receptor subunits. Science. 1994;266(5187):1045- 7.
Hubbard SR. Mechanistic Insights into Regulation of JAK2 Tyrosine Kinase. Front Endocrinol (Lausanne). 2017;8:361.
Lim CP, Cao X. Structure, function, and regulation of STAT proteins. Mol Biosyst. 2006;2(11):536-50.
Pharmacoeconomic Review Report: Tofacitinib (Xeljanz): (Pfizer Canada Inc.):. 2019.
Parmentier JM, Voss J, Graff C, Schwartz A, Argiriadi M, Friedman M, et al. In vitro and in vivo characterization of the JAK1 selectivity of upadacitinib (ABT-494). BMC Rheumatol. 2018;2:23.
Clinical Review Report: Upadacitinib (Rinvoq): (AbbVie):. 2020.
Guttman-Yassky E, Teixeira HD, Simpson EL, Papp KA, Pangan AL, Blauvelt A, et al. Once-daily upadacitinib versus placebo in adolescents and adults with moderate-to-severe atopic dermatitis (Measure Up 1 and Measure Up 2): results from two replicate double-blind, randomised controlled phase 3 trials. Lancet. 2021;397(10290):2151-68.
Reich K, Teixeira HD, de Bruin-Weller M, Bieber T, Soong W, Kabashima K, et al. Safety and efficacy of upadacitinib in combination with topical corticosteroids in adolescents and adults with moderate-to-severe atopic dermatitis (AD Up): results from a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2021;397(10290):2169-81.
Silverberg JI, Simpson EL, Thyssen JP, Gooderham M, Chan G, Feeney C, et al. Efficacy and Safety of Abrocitinib in Patients With Moderate-to-Severe Atopic Dermatitis: A Randomized Clinical Trial. JAMA Dermatol. 2020;156(8):863-73.
Simpson EL, Sinclair R, Forman S, Wollenberg A, Aschoff R, Cork M, et al. Efficacy and safety of abrocitinib in adults and adolescents with moderate-to-severe atopic dermatitis (JADE MONO-1): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial. Lancet. 2020;396(10246):255-66.
Crowley EL, Nezamololama N, Papp K, Gooderham MJ. Abrocitinib for the treatment of atopic dermatitis. Expert Rev Clin Immunol. 2020;16(10):955-62.
Armstrong A, Gooderham M, Warren RB, Papp K, Strober B, Thaçi D, et al. POS1042 EFFICACY AND SAFETY OF DEUCRAVACITINIB, AN ORAL, SELECTIVE TYROSINE KINASE 2 (TYK2) INHIBITOR, COMPARED WITH PLACEBO AND APREMILAST IN MODERATE TO SEVERE PLAQUE PSORIASIS: RESULTS FROM THE PHASE 3 POETYK PSO-1 STUDY. Annals of the Rheumatic Diseases. 2021;80(Suppl 1):795-6.
Chimalakonda A, Burke J, Cheng L, Catlett I, Tagen M, Zhao Q, et al. Selectivity Profile of the Tyrosine Kinase 2 Inhibitor Deucravacitinib Compared with Janus Kinase 1/2/3 Inhibitors. Dermatol Ther (Heidelb). 2021;11(5):1763-76.
Wrobleski ST, Moslin R, Lin S, Zhang Y, Spergel S, Kempson J, et al. Highly Selective Inhibition of Tyrosine Kinase 2 (TYK2) for the Treatment of Autoimmune Diseases: Discovery of the Allosteric Inhibitor BMS-986165. J Med Chem. 2019;62(20):8973-95.
Papp K, Gordon K, Thaçi D, Morita A, Gooderham M, Foley P, et al. Phase 2 Trial of Selective Tyrosine Kinase 2 Inhibition in Psoriasis. N Engl J Med. 2018;379(14):1313-21.
King B, Guttman-Yassky E, Peeva E, Banerjee A, Sinclair R, Pavel AB, et al. A phase 2a randomized, placebo-controlled study to evaluate the efficacy and safety of the oral Janus kinase inhibitors ritlecitinib and brepocitinib in alopecia areata: 24-week results. J Am Acad Dermatol. 2021;85(2):379-87.
Dhar TGM, Dyckman AJ. 5.12 – Evolution of Small-Molecule Immunology Research— Changes Since CMC II. In: Chackalamannil S, Rotella D, Ward SE, editors. Comprehensive Medicinal Chemistry III. Oxford: Elsevier; 2017. p. 395-419.
Ibrahim O, Bayart CB, Hogan S, Piliang M, Bergfeld WF. Treatment of Alopecia Areata With Tofacitinib. JAMA Dermatol. 2017;153(6):600-2.
Liu LY, Strassner JP, Refat MA, Harris JE, King BA. Repigmentation in vitiligo using the Janus kinase inhibitor tofacitinib may require concomitant light exposure. J Am Acad Dermatol. 2017;77(4):675-82.e1.
Papp KA, Bissonnette R, Gooderham M, Feldman SR, Iversen L, Soung J, et al. Treatment of plaque psoriasis with an ointment formulation of the Janus kinase inhibitor, tofacitinib: a Phase 2b randomized clinical trial. BMC Dermatol. 2016;16(1):15.
Bissonnette R, Papp KA, Poulin Y, Gooderham M, Raman M, Mallbris L, et al. Topical tofacitinib for atopic dermatitis: a phase IIa randomized trial. Br J Dermatol. 2016;175(5):902-11.
Bayart CB, DeNiro KL, Brichta L, Craiglow BG, Sidbury R. Topical Janus kinase inhibitors for the treatment of pediatric alopecia areata. J Am Acad Dermatol. 2017;77(1):167-70.
Zhou T, Georgeon S, Moser R, Moore DJ, Caflisch A, Hantschel O. Specificity and mechanism-of-action of the JAK2 tyrosine kinase inhibitors ruxolitinib and SAR302503 (TG101348). Leukemia. 2014;28(2):404-7.
Mackay-Wiggan J, Jabbari A, Nguyen N, Cerise JE, Clark C, Ulerio G, et al. Oral ruxolitinib induces hair regrowth in patients with moderate-to-severe alopecia areata. JCI Insight. 2016;1(15):e89790.
Loscocco GG, Vannucchi M, Paoli C, Franci A, Pieri L, Annunziato F, et al. Kaposi sarcoma in a patient treated with ruxolitinib. Ann Oncol. 2017;28(7):1670-1.
Tourlaki A, Benzecry V, Veraldi S, Brambilla L. Iatrogenic Kaposi sarcoma in a patient treated with ruxolitinib: A case report. J Dermatol. 2020;47(2):e38-e9.
Papp K, Szepietowski JC, Kircik L, Toth D, Eichenfield LF, Leung DYM, et al. Efficacy and safety of ruxolitinib cream for the treatment of atopic dermatitis: Results from 2 phase 3, randomized, double-blind studies. J Am Acad Dermatol. 2021;85(4):863-72.
Fridman JS, Scherle PA, Collins R, Burn TC, Li Y, Li J, et al. Selective inhibition of JAK1 and JAK2 is efficacious in rodent models of arthritis: preclinical characterization of INCB028050. J Immunol. 2010;184(9):5298-307.
Simpson EL, Forman S, Silverberg JI, Zirwas M, Maverakis E, Han G, et al. Baricitinib in patients with moderate-to-severe atopic dermatitis: Results from a randomized monotherapy phase 3 trial in the United States and Canada (BREEZE-AD5). J Am Acad Dermatol. 2021;85(1):62-70.
Olamiju B, Friedmann A, King B. Treatment of severe alopecia areata with baricitinib. JAAD Case Rep. 2019;5(10):892-4.
Tanimoto A, Ogawa Y, Oki C, Kimoto Y, Nozawa K, Amano W, et al. Pharmacological properties of JTE-052: a novel potent JAK inhibitor that suppresses various inflammatory responses in vitro and in vivo. Inflamm Res. 2015;64(1):41-51.
Nakagawa H, Nemoto O, Igarashi A, Saeki H, Kaino H, Nagata T. Delgocitinib ointment, a topical Janus kinase inhibitor, in adult patients with moderate to severe atopic dermatitis: A phase 3, randomized, double-blind, vehicle-controlled study and an open-label, long-term extension study. J Am Acad Dermatol. 2020;82(4):823-31.
Nakagawa H, Nemoto O, Igarashi A, Saeki H, Kabashima K, Oda M, et al. Delgocitinib ointment in pediatric patients with atopic dermatitis: A phase 3, randomized, double-blind, vehicle-controlled study and a subsequent open-label, long-term study. J Am Acad Dermatol. 2021;85(4):854-62.
Li B, Wan Q, Li Z, Chng WJ. Janus Kinase Signaling: Oncogenic Criminal of Lymphoid Cancers. Cancers (Basel). 2021;13(20).
Wu KJ, Huang JM, Zhong HJ, Dong ZZ, Vellaisamy K, Lu JJ, et al. A natural product-like JAK2/STAT3 inhibitor induces apoptosis of malignant melanoma cells. PLoS One. 2017;12(6):e0177123.
Pérez C, González-Rincón J, Onaindia A, Almaráz C, García-Díaz N, Pisonero H, et al. Mutated JAK kinases and deregulated STAT activity are potential therapeutic targets in cutaneous T-cell lymphoma. Haematologica. 2015;100(11):e450-3.
Zaretsky JM, Garcia-Diaz A, Shin DS, Escuin- Ordinas H, Hugo W, Hu-Lieskovan S, et al. Mutations Associated with Acquired Resistance to PD-1 Blockade in Melanoma. N Engl J Med. 2016;375(9):819-29.
Salas A, Hernandez-Rocha C, Duijvestein M, Faubion W, McGovern D, Vermeire S, et al. JAK-STAT pathway targeting for the treatment of inflammatory bowel disease. Nat Rev Gastroenterol Hepatol. 2020;17(6):323-37.
