Inhibitor of Pancreatic Cancer by RHIL1RA-Letter.

We have read the article with interest by Zhuang and colleagues (1) on the combination of IL1R antagonist and gemcitabine in gemcitabine-resistant pancreatic ductal adenocarcinoma (PDAC). The article showed that gemcitabine-induced NF-kB and ERK activation in gemcitabine-resistant PDAC cells can be reversed by anakinra, an FDA-approved IL1R antagonist. However, there are still some key points that should be discussed with more details. The mutational activity of KRAS has been detected in 85% to 90% of PDAC and 70% of KRAS-mutant PDAC with NF-kB activation. Mutations were found in the second base of codon 12 of KRAS in almost all pancreatic cancer cell lines, except Hs766T and BxPC-3 (2). However, the sensitivity of gemcitabine was not consistent with themutation of KRAS; both CFPAC-1 and BxPC-1 are sensitive to gemcitabine. SoNF-kB signal pathway, as a key downstream of KRAS, might be the critical point. As demonstrated by the authors, gemcitabine-resistant pancreatic cancer cell lines like AsPC-1 showed activation of NF-kB after the use of gemcitabine, which was considered as a pivotal mechanism of gemcitabine resistance. But unfortunately, previous studies demonstrate controversial opinions on the correlation between the activation of NF-kB and gemcitabine resistance in PDAC. In the study by Pan and colleagues (3), the authors found that NF-kB activity did not correlate with sensitivity to gemcitabine, and gemcitabine treatment did not activate NF-kB either in vitro or in vivo both in gemcitabine-sensitive/resistant pancreatic cancer cell lines. Our group also found that gemcitabine could reduce the activation of NF-kB both in BxPC-3/CFPAC-1 (gemcitabine sensitive) and AsPC-1/PANC-1 (gemcitabine resistant) cell lines. What is more, gemcitabine could not induce NF-kB activation in BxPC-3/GEM cell line in some studies (4), whichmeans that NF-kB activation was not a general result after gemcitabine treatment in different gemcitabine-resistant cell lines, even in the same pancreatic cancer cell line. All the results indicated that NFkB activation may not be a mechanism of gemcitabine resistance in PDAC, and further evidence is required. According to previous research, Ling and colleagues (5) revealed that KRAS-induced IL1a activated NF-kB and its target genes IL1a and p62 to initiate IL1a/p62 feedback loop, which may be an important mechanism between KRAS mutation and NF-kB activation in the development of PDAC. In conclusion, we congratulate Zhuang and colleagues: IL1a maybe a useful therapeutic target for a subset of pancreatic cancer, but we believe that its mechanism of reversing gemcitabine resistance remains controversial.