PAK1-Dependent Antitumor Effect of AAC-11-Derived Peptides on Sezary Syndrome Malignant CD4+ T Lymphocytes

Sezary syndrome is an aggressive form of cutaneous T-cell lymphoma characterized by the presence of a malignant CD4(+) T-cell clone in both blood and skin. Its pathophysiology is still poorly understood, and the development of targeted therapies is hampered by the absence of specific target proteins. AAC-11 plays important roles in cancer cell progression and survival and thus has been considered as an anticancer therapeutic target. In this study, we show that a peptide called RT39, comprising a portion of AAC-11.binding site to its protein partners coupled to the penetratin sequence, induces the specific elimination of the malignant T-cell clone both ex vivo on the circulating cells of patients with Sezary syndrome and in vivo in a subcutaneous xenograft mouse model. RT39 acts by direct binding to PAK1 that is overexpressed, located in the plasma membrane, and constitutively activated in Sezary cells, resulting in their selective depletion by membranolysis. Along with the absence of toxicity, our preclinical efficacy evidence suggests that RT39 might represent a promising alternative therapeutic tool for Sezary syndrome because it spares the nonmalignant immune cells and, contrary to antibody-based immunotherapies, does not require the mobilization of the cellular immunity that shows heavy deficiencies at advanced stages of the disease.

Automated summary

The study demonstrates that the peptide RT39 shows potential therapeutic effects in the specific elimination of the malignant T-cell clone in Sezary syndrome, by binding to PAK1 and inducing selective depletion of the cells through membranolysis. Additionally, RT39 displays good safety profile.