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IRAK4 mediates colitis-induced tumorigenesis and chemoresistance in colon cancer.

Aberrant activation of the NF-κB transcription factors underlies chemoresistance in various cancer types including colorectal cancer (CRC). Targeting the activating mechanisms, particularly with inhibitors to the upstream IκB kinase (IKK) complex, is a promising strategy to augment the effect of chemotherapy. However, clinical success has been limited largely due to low specificity and toxicities of tested compounds. In solid cancers, the IKK kinases is driven predominantly by the Toll-like/Interlekin-1 receptor family members, which signal through the Interleukin-1 Receptor-Associated Kinases (IRAKs), with isoform 4 (or IRAK4) being the most critical. The pathogenic role and therapeutic value of IRAK4 in CRC has not been investigated. We found that IRAK4 inhibition significantly abrogates colitis-induced neoplasm in APCMin/+ mice, and bone marrow transplant experiments showed an essential role of IRAK4 in immune cells during neoplastic progression. Chemotherapy significantly enhances IRAK4 and NF-κB activity in CRC cells through upregulating TLR9 expression, which can in turn be suppressed by IRAK4 and IKK inhibitors, suggesting a feedforward pathway that protects CRC cells from chemotherapy. Lastly, increased tumor phospho-IRAK4 staining or IRAK4 mRNA expression are associated with significantly worse survival in CRC patients. Our results support targeting IRAK4 to improve the effects of chemotherapy and outcomes in CRC.