Why is ruxolitinib a promising therapeutic option for patients with STAT3 gain-of-function (GOF)?¶
Answer: Ruxolitinib is a JAK1/2 inhibitor; by blocking JAK it prevents STAT3 phosphorylation and activation, targeting the pathway upstream of the gain-of-function defect.
STAT3 is part of the Janus kinase (JAK)/STAT pathway which is one of the most complex transcription regulators participating in a variety of physiological processes. It mediates signal transduction from the cell membrane to the nucleus in multiple intracellular and extracellular activities. Among the 7 members of the STAT protein family, STAT3 is a cytosolic protein that, upon activation by many pro-inflammatory cytokines, hormones and growth factors, is tyrosine-phosphorylated (pY705STAT3) by JAK. It then dimerizes and translocates to the nucleus to activate target genes transcription, Mcl1, c-Myc, cyclins D1 and D2, Bcl-xl among others. The STAT pathway is therefore involved in the regulation of crucial genes related to extremely widespread functions including cell proliferation, differentiation, survival, inflammation, immunity, and metastasis, thereby being central in many physiological and pathological processes.
— The constitutive activation of STAT3 gene and its mutations are at the crossroad between LGL leukemia and autoimmune disorders (Blood Cancer J 2024)