This finding is in the study “Intrinsic BET inhibitor resistance in SPOP-mutated prostate cancer is mediated by BET protein stabilization and AKT–mTORC1 activation,” published in the journal Nature Medicine.
BET proteins are expressed in most cells and play a role in activating the expression of cancer-promoting genes. Small-molecule inhibitors that target BET proteins have been developed and are currently in clinical trials as treatments for different types of cancer. But resistance to BET inhibitors has been widely reported in people with prostate cancer.
SPOP is an enzyme that works to degrade certain proteins. Analysis of whole-genome and exome sequencing studies, which are conducted to spot mutations, found that SPOP is the most frequently mutated gene in patients with primary prostate cancer. Interestingly, the mutations tend to be in the active domain of the protein, which indicates that a loss of SPOP degradation may play a role in the disease.
To further investigate the role of SPOP mutations in prostate cancer, researchers conducted experiments to determine the proteins that SPOP interacts with. While they discovered that SPOP interacts with many proteins, BET proteins were at the top of the list. The work also showed that SPOP not only binds to BET proteins but also induces their degradation.
Researchers then demonstrated that mutating SPOP led to a decrease in the binding and degradation of BET proteins. This resulted to high BET protein levels in cells, indicating that SPOP mutations cause an accumulation of BET proteins. SPOP-mutated prostate cancer samples studied also showed high levels of BET proteins.
The team, working with prostate cancer cells with SPOP mutations, also found increased resistance to BET inhibitors, which was attributed to the excessive levels of BET proteins in those cells.
BET inhibitor resistance and SPOP mutations were also seen in genes that activated the AKT-mTORC1 signaling pathway, a known cancer-promoting pathway that results in increased cell growth.
As the AKT-mTORC1 pathway is activated in these cells, further experiments found that agents designed to block the AKT pathway — such as the AKT inhibitor ipatasertib — used along with BET inhibitors, can help overcome BET inhibitor resistance in prostate cancer cells with SPOP mutations.
These findings not only provide the mechanism behind the BET resistance that is observed clinically but also provide SPOP mutations as a potential biomarker for helping physicians identify the correct treatment to administer their patients, the reserachers said.
“These findings have important implications for prostate cancer treatment, because SPOP mutation or elevated BET protein expression can now be used as biomarkers to improve outcome of BET inhibitor-oriented therapy of prostate cancer with SPOP mutation or BET protein overexpression,” Haojie Huang, the study’s senior author and a molecular biologist at the Mayo Clinic’s Center for Biomedical Discovery, said in a press release.