PAK1-dependent anti-tumor effect of AAC-11-derived peptides on Sézary syndrome malignant CD4+ T lymphocytes.

Abstract

Sézary 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 hampered by the absence of specific target proteins. AAC-11 (anti-apoptosis clone-11) plays important roles in cancer cell progression and survival and thus has been considered as an anticancer therapeutic target. Here 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 Sézary patients circulating cells and in vivo in a sub-cutaneous xenograft mouse model. RT39 acts by direct binding to p21-activated kinase 1 (PAK1) that is over-expressed, plasma membrane-located and constitutively activated in Sézary cells, resulting in their selective depletion by membranolysis. Along with the absence of toxicity, our preclinical efficacy evidences suggest that RT39 might represent a promising alternative therapeutic tool for Sézary syndrome as it spares the non-malignant immune cells and, unlike antibody-based immunotherapies, does not require the mobilization of the cellular immunity that shows heavy deficiencies at advanced stages of the disease.