Journal
JOURNAL OF HEMATOLOGY & ONCOLOGY
Volume 15, Issue 1, Pages -Publisher
BMC
DOI: 10.1186/s13045-022-01286-4
Keywords
Pancreatic cancer; IL1RAP; IRAK4
Categories
Funding
- CA200561 T32 training grant
- Einstein Training Program in Stem Cell Research from the Empire State Stem Cell Fund through New York State Department of Health [C34874GG]
- GI SPORE grant [P50CA221707]
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IL1RAP is an important regulator in the development of pancreatic cancer and its overexpression is associated with poor prognosis in pancreatic cancer patients. Silencing IL1RAP and inhibiting its downstream IRAK4 can reduce the growth and invasive ability of pancreatic cancer cells.
Advanced pancreatic ductal adenocarcinoma (PDAC) is usually an incurable malignancy that needs newer therapeutic targets. Interleukin-1 receptor accessory protein (IL1RAP) is an innate immune mediator that regulates activation of pro-inflammatory and mitogenic signaling pathways. Immunohistochemistry on tissue microarrays demonstrated expression of IL1RAP in majority of human PDAC specimens and in murine pancreatic tumors from K-Ras(G122D)/p53(R172H)/PDXCre (KPC) mice. Single cell RNA-Seq analysis of human primary pre-neoplastic lesions and adenocarcinoma specimens indicated that overexpression occurs during carcinogenesis. IL1RAP overexpression was associated with worse overall survival. IL1RAP knockdown significantly reduced cell viability, invasiveness, and clonogenic growth in pancreatic cancer cell lines. Inhibition of the downstream interleukin-1 receptor-associated kinase 4 (IRAK4) using two pharmacologic inhibitors, CA-4948 and PF06650833, resulted in reduced growth in pancreatic cancer cell lines and in xenograft models.
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