Local control of tumor growth is partly achieved by considering radiation induced cell death as a result of damage to cell membranes and DNA. However, the efficacy of radiotherapy remains limited due to intense tumor resistance. The molecular mechanisms underlying radiation resistance of pancreatic cancer are not fully understood. The mammalian target of rapamycin, a well known serine threonine kinase, is identified Inhibitors,Modulators,Libraries as a down stream target of PI3K Akt survival pathway and functions as a central regulator of cell growth, proliferation and survival. Accumulating evidence demonstrated that mTOR was dysregulated in various cancers, its over expression and over activation contribute to can cer progression and drug resistance. As a result, Inhibitors,Modulators,Libraries mTOR inhibitors represent a promising therapeutic ap proach for cancer and solid tumors.

The first generation mTOR inhibitors, like rapamycin and its analogs everolimus, temsirolimus and ridaforolimus, have been developed as cancer therapeutic agents. However, they are insufficient for achieving a broad and robust anticancer effect due to the feedback Inhibitors,Modulators,Libraries of AKT activation via up regulating insulin like growth factor 1. AZD 8055, a novel ATP competitive inhibitor of mTOR kinases, besides preventing feedback to AKT, potently showed ex cellent selectivity against all class I PI3K isoforms and other members of the PI3K like kinase family. AZD8055 is currently tested in phase I clinical trials as an anti tumor drug. Prior Inhibitors,Modulators,Libraries studies reported that com bination of mTOR inhibitor RAD001 with radiotherapy can delay solid tumor growth in vitro and in vivo due to synergistic anti angiogenic and anti vascular effects, but the detail mechanisms remain poorly defined.

Here, we wonder whether mTOR inhibitor AZD8055 can also amp lify the radiotherapeutic effects in pancreatic cancers. MicroRNAs are a class of small non coding RNAs which play important roles in gene regulation by targeting mRNA in a sequence specific manner, and their dysregulations are a common feature Inhibitors,Modulators,Libraries in tumorigenesis and drug selleckbio resistance. Numerous studies have shown that miR 99b, miR 100, miR 199a 3p, miR 451, miR 144 and miR 101 can directly or indirectly mediate mTOR ex pression, and reduction of these miRNAs was connected with the elevated levels of mTOR in prostate cancer and endometrial carcinoma. However, it is still not clear whether these miRNAs can be regulated by radiation and be connected with aberrant mTOR activa tion in pancreatic cancer. In this study, we identified that mTOR is positively regulated by radiation in both human pancreatic biopsy specimens and cell lines, and this mTOR upregulation is promoted by radiation induced miR 99b downregu lation.