Recent research has uncovered a new cause of treatment resistance in prostate cancer, which may improve targeted therapy efforts.
Mutations within the SPOP gene are the most frequently documented genetic changes in primary prostate cancer. SPOP mutations drive tumor resistance to bromodomain and extra-terminal domain (BET)-inhibitors, which are designed to prevent the action of BET proteins – promotors of abnormal cancer cell growth. BET-inhibitors have shown promise in clinical trials, but drug resistance often develops, and improving treatment options for prostate cancer is necessary.
Haojie Huang, PhD, molecular biologist, Center for Biomedical Discovery, Mayo Clinic (Rochester, MN), and colleagues sought to better understand the relationship between SPOP mutations and BET-inhibitor resistance. Researchers reinforced the previous notion that SPOP mutations stabilize BET proteins against any action from BET-inhibitors, thus promoting cancer cell proliferation, invasion, and survival.
Findings from the study were published in Nature Medicine (online August 14, 2017; doi: 10.1038/nm.4379). Authors of the study disclosed four major discoveries:
- BET proteins (BRD2, BRD3 and BRD4) are true degradation substrates of SPOP.
- SPOP mutations cause elevation of BET proteins in prostate cancer patient specimens.
- Expression of SPOP mutants leads to BET-inhibitor resistance and activation of the AKT-mTORC1 pathway that promotes cancerous cell growth and survival.
- Co-administration of AKT inhibitors overcomes BET inhibitor resistance in SPOP-mutated prostate cancer.
"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," said Dr Huang in a statement (August 14, 2017).
Authors of the study further disclosed that Mayo Clinic Ventures—the technology commercialization arm of the clinic—has a patent application in place for this prostate cancer biomarker and therapeutic technology.—Zachary Bessette