Perturbation-based screening identified multiple compounds capable of reversing these interferon-amplified signatures, and in vitro experiments demonstrated that alpinetin and momelotinib suppress interferon-γ signaling through distinct STAT1-and JAK-STAT-dependent mechanisms. irAEs may arise from the convergence of pre-existing myeloid inflammation and interferon-driven lymphocyte activation before therapy. Our study provides a predictive framework for identifying high-risk patients and highlights mechanistically grounded compounds for potential irAE mitigation.
Momelotinib demonstrated meaningful clinical benefit and acceptable safety in cytopenic patients pretreated with ruxolitinib, which supports its role after ruxolitinib failure.
1 month ago
Retrospective data • Journal • Real-world evidence
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JAK2 (Janus kinase 2) • JAK1 (Janus Kinase 1) • ACVR1 (Activin A Receptor Type 1)
Unmet needs include standardized endpoints, biologically stratified trials, and validation of hemoglobin and transfusion responses as markers. Strategies like momelotinib plus luspatercept, earlier intervention, and new molecular therapies could turn treatment from palliation to durable control and disease modification.
In conclusion, ruxolitinib was the most potent, and selective JAKinib with no relevant effects in JAK2-independent cells. In contrast, fedratinib, pacritinib, and momelotinib inhibited many other kinases and inhibited cell growth by JAK2-unrelated mechanisms at clinically relevant concentrations.
This results in a better response to the JAK1 inhibitor momelotinib, highlighting RNA dicing's role in patient stratification. Our findings show that RNA dicing diversifies mRNA products, significantly impacting biological functions.