The Mechanisms of Resistance to JAK Inhibitors in Lymphoid Leukemias: A Scoping Review of Evidence from Preclinical Models and Case Reports.

The use of JAK inhibitors (JAKi) represents a promising therapeutic approach for patients with lymphoid leukemias (Lym-L). Clinical trials are ongoing to evaluate the safety and efficacy of JAK inhibitors. Over the last years, there have been reports of preclinical Lym-L models that developed JAKi resistance, and reports of patients treated with JAKi who experienced treatment failure. Although evidence shows that there are diverse JAKi mechanisms, no review studies have been performed that summarize and discuss this information. This scoping review aimed to provide an updated overview of the mechanisms underlying JAKi molecular resistance in Lym-L. According to a scoping review PRISMA guidelines, a search was conducted in the PubMed and Europe PMC databases for studies published from 2010 to 2024. We included articles that described the molecular resistance to JAKi in Lym-L preclinical models or patients. The search was complemented by a review of laboratory-engineered resistant mutations in genomic datasets to obtain more information about their presence in patients with Lym-L. Twenty-two articles were eligible for this review, and six different mechanisms of molecular resistance were identified: (1) point mutations in the kinase domain, (2) cooperation between double-JAK mutants, (3) inactivation of phosphatases, (4) evasion of JAK inhibition due to trans-phosphorylation of JAK family proteins, (5) upregulation of pro-survival proteins, and (6) activation of kinase cross-signaling pathways. The integrated evidence enabled the identification of specific mechanisms of molecular resistance to JAKi in Lym-L, as well as promising therapeutic approaches to prevent them. These include selecting a sensitive JAKi, choosing an effective dosage regimen, and combining inhibitory molecules.