Molecular Determinants of Hormone-Refractory Prostate Cancer.

摘要

We have performed a high throughput, in vivo genetic screen to identify kinases that permit androgen-dependent transformed prostate epithelial cells (LHSR-AR cells) to form tumors in female animals. In addition to known prostate cancer oncogenes and mediators of androgen independence (mutated KRAS, constitutively active MEK, RAF1, ERBB2, AKT1, PIM1 and PIM2), overexpression of the Never In Mitosis A (NIMA) related kinase 6 (NEK6) reproducibly yielded androgen-independent tumors. NEK6 is overexpressed in prostate cancer cell lines compared to their normal counterparts and is overexpressed in a subset of human prostate cancers. Expression of NEK6 confers castration resistance to established tumors in male mice, and suppressing NEK6 expression restores sensitivity to castration. Castration-resistant tumors generated through NEK6 overexpression are predominantly squamous in histology and do not express androgen receptor (AR), and NEK6 does not activate AR signaling. Phosphoproteome and interactome analysis reveals the transcription factors FOXJ2 and NCOA5, as well as the kinases CK1 and YES1 to be novel substrates. The gene expression profile mediated by NEK6 overexpression in tumors from castrated mice demonstrates elements of both differentiation and immune signaling, and phosphomimic forms of FOXJ2, YES1, and CK1 (but not NCOA5) recapitulate elements of this signature, particularly CK1 with markers of squamous differentiation. These studies reveal a novel mechanism of resistance in androgen pathway independent prostate cancer (APIPC).