Mechanisms of kinase inhibitor resistance in subtypes of cutaneous T-cell lymphomas

Cutaneous T-cell lymphomas (CTCLs) comprise a heterogeneous group of skin-homing T-cell malignancies with limited curative options. Recent genomic studies have identified recurrent alterations in tyrosine kinase signaling pathways in aggressive CTCL subtypes, particularly primary cutaneous aggressive epidermotropic cytotoxic T-cell lymphoma (PCAETL) and primary cutaneous gamma/delta T-cell lymphoma (PCGDTL). Changes include kinase fusions and activating mutations involving JAK/STAT and FGFR pathways and provide a rationale for targeted therapy. Early clinical experience with tyrosine kinase inhibitors (TKIs) such as ruxolitinib, cerdulatinib, and pemigatinib demonstrated meaningful but frequently transient responses. Acquired resistance commonly arises through secondary kinase domain mutations, including canonical gatekeeper substitutions and cooperative mutations across paralogous kinases, with adverse events preventing continued treatment. Structural modeling supports steric interference and altered ATP affinity as key mechanisms limiting drug efficacy. Collectively, these findings reveal kinase addiction as a therapeutic vulnerability in selected CTCL subtypes but also underscore predictable adaptive resistance. Durable responses will likely require molecular stratification, longitudinal genomic monitoring, and local application of rational combination strategies. Aggressive CTCL thus represents a model for precision oncology in dermatology, where mechanistic insight can guide next-generation therapeutic approaches.