Described in the journal Science Signaling, specific populations of prostate cancer cells are uniquely resistant to inhibitors of the PI3K pathway.

This alarming population of drug-resistant cells was found to harbor high levels of a protein known as 4EBP1, an important player in protein production. The authors found that high 4EBP1 levels decrease protein synthesis within cancer cells and make them immune to PI3K pathway inhibitors.

When the researchers genetically manipulated these cells to reduce 4EBP1, protein production was restored and the tumor cells once again became sensitive to drug treatment.

"By measuring 4EBP1 and protein-synthesis rates, we can potentially identify tumors that are resistant to PI3K pathway inhibitors," author said. This could be used to predict which prostate cancer patients might benefit most from this class of drugs and those who should not waste precious time with treatments that are likely to fail.

Using tumor samples from an ongoing clinical trial that is testing an experimental PI3K pathway inhibitor known as buparlisib, orBKM120, for men with prostate cancer, the researchers saw that 4EBP1 levels jumped in tumors following treatment. The author points to these findings as substantiation of the clinical relevance of their discoveries in the laboratory in mouse models and cancer cell lines.

According to the author, "the next step is to understand how high levels of 4EBP1 and low protein-synthesis rates drive drug resistance," and to develop new treatment strategies that either increase protein production rates to drug-sensitive levels or suppress them to levels intolerable to cancers.

http://www.fredhutch.org/en/news/center-news/2015/11/a-doctors-quest-to-unlock-answers-about-prostate-cancer.html