Augmentation of therapeutic responses in melanoma by inhibition of IRAK-1,-4
Menée sur des lignées cellulaires, sur 242 échantillons tumoraux prélevés sur des patients atteints d'un mélanome et à l'aide de xénogreffes, cette étude suggère que l'inhibition des kinases IRAK-1/4 permet d'augmenter la réponse à un traitement par vinblastine
Toll-like receptors (TLR) are expressed by a variety of cancers, including melanoma, but their functional contributions in cancer cells are uncertain. To approach this question, we evaluated the effects of stimulating or inhibiting the TLR/IL-1 receptor-associated kinases IRAK-1 and IRAK-4 in melanoma cells where their functions are largely unexplored. TLRs and TLR-related proteins were variably expressed in melanoma cell lines, with 42% expressing activated phospho-IRAK-1 constitutively and 85% expressing high levels of phospho-IRAK-4 in the absence of TLR stimulation. Immunohistochemical evaluation of melanoma tumor biopsies (n=242) revealed two distinct patient populations, one which expressed p-IRAK-4 levels similar to normal skin (55%) and one with significantly higher levels than normal skin (45%). Levels of p-IRAK-4 levels did not correlate with clinical stage, gender or age, but attenuating IRAK-1/4 signaling with pharmacological inhibitors or siRNA enhanced cell death in vitro in combination with vinblastine. Moreover, in a xenograft mouse model of melanoma, the combined pharmacological treatment delayed tumor growth and prolonged survival compared to subjects receiving single agent therapy. We propose p-IRAK-4 as a novel inflammation and pro-survival marker in melanoma with the potential to serve as a therapeutic target to enhance chemotherapeutic responses.