Predicting the response of pancreatic cancer to a new class of cancer drugs
Cancer patients often respond differently to different drugs. Identifying biomarkers that can predict a patient’s response to a given therapeutic will help treat only patients who will positively respond to that therapy. This will spare patients from wasting time and from suffering from unnecessary side effects. Bromodomain and extraterminal domain (BET) proteins are known to play an important role in driving cancer development. BET inhibitors are a new class of drugs that show promise in preclinical studies in a number of cancers including pancreatic cancer. In this study, we sought to identify potential biomarkers that would predict pancreatic cancer patients’ response to BET inhibitors. A database of pancreatic cancer cell lines containing their gene expression profiles and drug sensitivity data was used to select cell lines and genes of interest that correlate with the BET inhibitor I-BET-762. The expression of two genes, SLN and MEIS2, was found to correlate with cell sensitivity to I-BET-762 – cell lines with high expression of SLN are resistant to the drug whereas cell lines with high expression of MEIS2 are highly sensitive to the drug. To confirm the bioinformatics analysis results we selected two pancreatic cell lines Panc08.13, which is sensitive and Pa-Tu8902, which is resistant to the BET inhibitor for further study. The sensitivity of the two cell lines to BET inhibitors were first confirmed for I-BET-762 as well as two other BET inhibitors, JQ1 and OTX-015 using a cell proliferation assay. Pa-Tu8902 is 110 fold more resistant to the BET inhibitors than Panc08.13. The expression levels of two candidate genes, SLN and MEIS2 were also measured using RT-PCR and compared to their drug sensitivity. We found that MEIS2 expression to be 2.5 fold higher in the sensitive cell line Panc08.13 compared to the resistant cell line Pa-Tu8902, confirming that the high MEIS2, could predict high sensitivity to BET inhibitors. However, there was no difference in SLN expression levels between the sensitive and resistant cell lines, indicating that SLN expression is probably not a good biomarker for predicting sensitivity. Finally, treatment with I-BET-762 caused an eight-fold decrease in the MEIS2 expression in Panc08.13 cells. This result further suggests that MEIS2 is a potential target of BET inhibitors such as I-BET-762.