To define mechanisms of acquired resistance to tyrosine kinase inhibitors (TKIs) in primary cutaneous aggressive epidermotropic cytotoxic T-cell lymphoma (PCAETL) and primary cutaneous gamma/delta T-cell lymphoma (PCGDTL), highlighting the significance of these mechanisms for improving treatment strategies.
Key Findings:
PCAETL and PCGDTL exhibit recurrent kinase fusions and activating mutations in JAK/STAT and FGFR pathways, with JAK2 fusions indicating a unique role in oncogenic signaling.
Resistance to TKIs often arises from secondary kinase domain mutations and adverse events necessitating dose reductions, complicating treatment efficacy.
JAK2 fusions are prevalent in PCAETL, suggesting a critical target for future therapeutic strategies.
Interpretation:
Kinase addiction presents a therapeutic vulnerability in aggressive CTCL subtypes, but adaptive resistance mechanisms complicate treatment outcomes, necessitating innovative approaches.
Limitations:
Resistance mechanisms may vary among patients, complicating treatment strategies and necessitating personalized approaches.
Limited long-term data on the efficacy of TKIs in CTCL restricts understanding of their potential benefits.
Conclusion:
Durable responses in CTCL will require molecular stratification, genomic monitoring, and rational combination therapies to overcome resistance, emphasizing the need for ongoing research.
