FKBP5 as a Selection Biomarker for Gemcitabine and Akt Inhibitors in Treatment of Pancreatic Cancer

Abstract

We have recently shown that the immunophilin FKBP5 (also known as FKBP51) is a scaffolding protein that can enhance PHLPP-AKT interaction and facilitate PHLPP-mediated dephosphorylation of Akt Ser473, negatively regulating Akt activation in vitro. Therefore, FKBP5 might function as a tumor suppressor, and levels of FKBP5 would affect cell response to chemotherapy. In the current study, we have taken a step forward by using a pancreatic cancer xenograft mice model to show that down regulation of FKBP5 in shFKBP5 xenograft mice promotes tumor growth and resistance to gemcitabine, a phenomenon consistent with our previous findings in pancreatic cell lines. In addition, we also found that inhibitors targeting the Akt pathway, including PI3K inhibitor, Akt inhibitor and mTOR inhibitor had a different effect on sensitization to gemcitabine and other chemotherapeutic agents in cell lines, with a specific Akt inhibitor, triciribine, having the greatest sensitization effect. We then tested the hypothesis that addition of triciribine can sensitize gemcitabine treatment, especially in shFKBP5 pancreatic cancer xenograft mice. We found that combination treatment with gemcitabine and triciribine has a better effect on tumor inhibition than either drug alone (p<0.005) and that the inhibition effect is more significant in shFKBP5 xenograft mice than wt mice (p<0.05). These effects were correlated with level of Akt 473 phosphorylation as well as proliferation rate, as indicated by Ki67 staining in xenograft tumor tissues. These results provide evidence in support of future clinical trials designed to tailor therapy based on our observations.

Thiopurine Pharmacogenomics: Association of Snps with Clinical Response and Functional Validation of Candidate Genes

“…However, it should be emphasized once again that this LCL model system has already repeatedly demonstrated its power to generate pharmacogenomic hypotheses [28,32,33,46] and to pursue pharmacogenomic hypotheses from clinical GWAS [31,34,47]. The present study shows that SNPs identified during GWAS performed with this model system may help lead us to genomic regions of possible importance for thiopurine treatment response.…”

Turning Off AKT: PHLPP as a Drug Target

“…This led to the proposal that the scaffold facilitates termination of AKT signaling by PHLPP, allowing greater sensitivity to chemotherapeutics (62; 72). This hypothesis is strongly supported by studies using a pancreatic mouse xenograft model that show that down-regulation of FKBP5 promotes tumor growth and resistance to the chemotherapeutic gemcitabine (73). Thus, levels of FKBP5 serve as a biomarker for the chemotherapeutic responsiveness in pancreatic cancer.…”

FKBPs and the Akt/mTOR pathway

“…34,35 Notably, FKBP51 was found to act as a scaffolding protein to facilitate the dephosphorylation of Akt by the phosphatase PHLPP. 36,37 In cells, the interaction of FKBP51 with Akt was in part mediated by Hsp90 (FKBP51 binds to Hsp90 via its TPR domain and Akt is an established Hsp90 client). 35 However, FKBP51 could also interact with Akt directly.…”