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Cancer Res. 2012 Dec 1;72(23):6209-16. doi: 10.1158/0008-5472.CAN-12-0337. Epub 2012 Oct 4.

Augmentation of therapeutic responses in melanoma by inhibition of IRAK-1,-4.

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Marlene and Stewart Greenebaum NCI Cancer Center, University of Maryland, Baltimore, MD 21201-1559, USA.


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 that 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 attenuated IRAK-1,-4 signaling with pharmacologic inhibitors or siRNA-enhanced cell death in vitro in combination with vinblastine. Moreover, in a xenograft mouse model of melanoma, the combined pharmacologic treatment delayed tumor growth and prolonged survival compared with subjects receiving single agent therapy. We propose p-IRAK-4 as a novel inflammation and prosurvival marker in melanoma with the potential to serve as a therapeutic target to enhance chemotherapeutic responses.

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