Defining and Targeting the Oncogenic Drivers of Neuroendocrine Prostate Cancer
Authors: Brett S. Carver
Journal: Cancer Cell (2016)

In this issue of Cancer Cell, Lee et al., 2016Lee J.K. Phillips J.W. Smith B.A. Park J.W. Stoyanova T. McCaffrey E.F. Baertsch R. Sokolov A. Meyerowitz J.G. Mathis C. et al.Cancer Cell. 2016; 29 (this issue): 536-547Abstract Full Text Full Text PDF PubMed Scopus (214) Google Scholar define the biologic role of MYCN in promoting prostate tumorigenesis and development of a neuroendocrine phenotype. This has important implications for the clinical management of neuroendocrine prostate cancer as Aurora A kinase inhibitors promoting N-Myc destabilization progress in the clinic. In this issue of Cancer Cell, Lee et al., 2016Lee J.K. Phillips J.W. Smith B.A. Park J.W. Stoyanova T. McCaffrey E.F. Baertsch R. Sokolov A. Meyerowitz J.G. Mathis C. et al.Cancer Cell. 2016; 29 (this issue): 536-547Abstract Full Text Full Text PDF PubMed Scopus (214) Google Scholar define the biologic role of MYCN in promoting prostate tumorigenesis and development of a neuroendocrine phenotype. This has important implications for the clinical management of neuroendocrine prostate cancer as Aurora A kinase inhibitors promoting N-Myc destabilization progress in the clinic. Androgen deprivation therapy is the first-line management of metastatic prostate cancer, resulting in a delay in disease progression, although the vast majority of these tumors develop acquired castrate-resistant disease secondary to genomic alterations of the androgen receptor (AR) axis. These findings have led to the development of several second-generation AR targeting strategies, including enzalutamide and abiraterone acetate, which have been shown to improve overall survival for men with castrate-resistant prostate cancer (de Bono et al., 2011de Bono J.S. Logothetis C.J. Molina A. Fizazi K. North S. Chu L. Chi K.N. Jones R.J. Goodman Jr., O.B. Saad F. et al.COU-AA-301 InvestigatorsN. Engl. J. Med. 2011; 364: 1995-2005Crossref PubMed Scopus (3396) Google Scholar, Scher et al., 2012Scher H.I. Fizazi K. Saad F. Taplin M.E. Sternberg C.N. Miller K. de Wit R. Mulders P. Chi K.N. Shore N.D. et al.AFFIRM InvestigatorsN. Engl. J. Med. 2012; 367: 1187-1197Crossref PubMed Scopus (3401) Google Scholar). Both of these therapies are associated with the emergence of resistance, yet the mechanisms through which resistance evolves appears to be more diverse than observed in the first-line setting. These mechanisms include novel mutations in the androgen receptor, overexpression of the glucocorticoid nuclear hormone receptor, and the increasing appreciation of de-differentiation of prostate adenocarcinoma to acquired AR-independent neuroendocrine (small-cell carcinoma) disease (Arora et al., 2013Arora V.K. Schenkein E. Murali R. Subudhi S.K. Wongvipat J. Balbas M.D. Shah N. Cai L. Efstathiou E. Logothetis C. et al.Cell. 2013; 155: 1309-1322Abstract Full Text Full Text PDF PubMed Scopus (654) Google Scholar). Previous studies have reported the incidence of neuroendocrine phenotypes in approximately 1% of primary prostate cancers and up to 25%–30% of lethal metastatic castrate-resistant prostate cancers. Traditionally, neuroendocrine prostate cancers are managed clinically with cisplatin-based chemotherapy regimens, with poor overall survival. However, as our identification and understanding of the oncogenic drivers of this phenotype emerge, there is hope for the development of much needed novel targeted therapies. Recent genomic profiling studies have demonstrated that prostate cancers with a neuroendocrine phenotype are enriched for loss of RB, loss or mutation of TP53, loss of AR and AR target gene expression, and overexpression of MYCN and AURKA (Beltran et al., 2016Beltran H. Prandi D. Mosquera J.M. Benelli M. Puca L. Cyrta J. Marotz C. Giannopoulou E. Chakravarthi B.V. Varambally S. et al.Nat. Med. 2016; 22: 298-305Crossref PubMed Scopus (889) Google Scholar). Importantly, these genomic profiling studies reveal that acquired neuroendocrine disease appears to evolve from castrate-resistant adenocarcinoma, as many of these neuroendocrine prostate cancers harbor the ERG genomic rearrangement and other canonical alteration in prostate adenocarcinoma, suggesting that they were once AR dependent. The current study by Lee et al. demonstrates the oncogenic role of MYCN in prostate carcinogenesis and neuroendocrine trans-differentiation. Using an established assay to isolate basal cells from normal human prostate, the authors demonstrate that overexpression of MYCN and myrisylated AKT promote tumorigenesis across the phenotypes of adenocarcinoma, squamous cell differentiation, and neuroendocrine differentiation (Lee et al., 2016Lee J.K. Phillips J.W. Smith B.A. Park J.W. Stoyanova T. McCaffrey E.F. Baertsch R. Sokolov A. Meyerowitz J.G. Mathis C. et al.Cancer Cell. 2016; 29 (this issue): 536-547Abstract Full Text Full Text PDF PubMed Scopus (214) Google Scholar). In this pre-clinical setting, only basal cells and not luminal cells were capable of transforming, which is in contrast to some of the previous pre-clinical and clinical findings. Furthermore, the authors demonstrate in pre-clinical xenograft tumors that following surgical castration there is enrichment for the resistant neuroendocrine phenotype, and depletion of N-Myc through inducible small hairpin RNA knockdown results in tumor regressions, highlighting the dependency of these tumors on MYCN and thus making it an attractive target for therapy. In accordance with these findings, Lee et al. evaluated the therapeutic efficacy of several Aurora A kinase inhibitors and find that CD532, a novel AURKA inhibitor, results in a significant reduction in MYCN protein levels and decreased tumor burden in pre-clinical models driven by MYCN overexpression. Interestingly, this effect was not observed with MLN8237, which is currently in early-phase clinical trials, and downregulation of MYCN protein levels did not appear to be dependent on AURKA kinase activity. While the current study establishes the oncogenic and potential therapeutic role of MYCN in neuroendocrine prostate cancer, it is still not established as to what is the precise cell of origin for metastatic neuroendocrine prostate cancer. The clinical and genomic profiling data suggest that in a minority of cases neuroendocrine prostate cancers may originate de novo from a small population of neuroendocrine cells present in the prostate, while in the majority of cases these tumors diverge from a population of luminal-derived metastatic castrate-resistant adenocarcinoma. This has important implications that may impact clinical response to inhibitors targeting the MYCN pathway, as the current models developed by Lee and colleagues lack the molecular complexity observed in metastatic prostate cancer. Thus, in the setting of metastatic castrate-resistant prostate cancer, it will be important to better define how concomitant molecular alterations in oncogenes or tumor suppressors that evolve during and are maintained after a luminal differentiated state may impact response to target therapies, which may allow for better patient selection and combinatorial drug development as future clinical trials move forward. N-Myc Drives Neuroendocrine Prostate Cancer Initiated from Human Prostate Epithelial CellsLee et al.Cancer CellMarch 31, 2016In BriefLee et al. establish N-Myc as a driver of neuroendocrine prostate cancer (NEPC) and a target for intervention. N-Myc and activated AKT1 are sufficient to transform human prostate epithelial cells to prostate adenocarcinoma and NEPC, both of which can be derived from a common epithelial precursor. Full-Text PDF Open Archive