CD73, a cell surface-bound
nucleotidase, facilitates extracellular
adenosine formation by hydrolyzing 5'-AMP to
adenosine. Several studies have shown that CD73 plays an essential role in immune escape, cell proliferation and
tumor angiogenesis, making it an attractive target for
cancer therapies. However, there are limited clinical benefits associated with the mainstream enzymatic inhibitors of CD73, suggesting that the mechanism underlying the role of CD73 in
tumor progression is more complex than anticipated, and further investigation is necessary. In this study, CD73 is found to overexpress in the cytoplasm of pancreatic ductal
adenocarcinoma (PDAC) cells and promotes
metastasis in a
nucleotidase-independent manner, which cannot be restrained by the CD73
monoclonal antibodies or small-molecule enzymatic inhibitors. Furthermore, CD73 promotes the
metastasis of PDAC by binding to the
E3 ligase TRIM21, competing with the Snail for its binding site. Additionally, a CD73 transcriptional inhibitor,
diclofenac, a non-steroidal anti-inflammatory
drug, is more effective than the CD73 blocking antibody for the treatment of PDAC
metastasis.
Diclofenac also enhances the therapeutic efficacy of
gemcitabine in the spontaneous KPC (LSL-KrasG12D/+ , LSL-Trp53R172H/+ , and Pdx-1-Cre)
pancreatic cancer model. Therefore,
diclofenac may be an effective anti-CD73
therapy, when used alone or in combination with
gemcitabine-based
chemotherapy regimen, for metastatic PDAC.