Molecular Determinants of Hormone Refractory Prostate Cancer
Annual summary rept. 1 Jul 2012-30 Jun 2013
DANA-FARBER CANCER INST BOSTON MA
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We have performed a high throughput, in vivo genetic screen to identify kinases that permitted androgen-dependent transformed prostate epithelial cells LHSR-AR cells to form tumors in female animals. In addition to known prostate cancer oncogenes, Never In Mitosis A NIMA related kinase 6 NEK6 reproducibly yielded androgen-independent tumors in female mice. NEK6 can confer castration resistance to established tumors in male mice, and inactivating its expression can restore sensitivity to castration. Castration-resistant tumors generated through NEK6 overexpression are predominantly squamous in histology and AR-negative, and NEK6 does not activate AR signaling. NEK6 overexpression leads to phosphorylation of RPS6KB1 and SGK1, and these two genes along with a novel identified substrate, FOXJ2, are essential for NEK6-mediated androgen-independent tumor formation. NEK6 is located on a region of recurrent copy number gain on chromosome 9q33.3 in human prostate cancer, and NEK6 overexpression in tumor microarrays and the TCGA data set correlates with more aggressive disease. NEK6 and its downstream effectors are thus potential novel therapeutic targets in CRPC.
- Genetic Engineering and Molecular Biology
- Medicine and Medical Research