- Email: [email protected]
Defining and Targeting the Oncogenic Drivers of Neuroendocrine Prostate Cancer
Cancer Cell
Previews Park, E.J., Lee, J.H., Yu, G.Y., He, G., Ali, S.R., Holzer, R.G., Osterreicher, C.H., Takahashi, H., and Karin, M. (2010). Cell 140, 197–208.
Wang, Q., Yu, W.-N., Chen, X., Peng, X.D., Jeon, S.-M., Birnbaum, M.J., Guzman, G., and Hay, N. (2016). Cancer Cell 29, this issue, 523–535.
Vivanco, I., and Sawyers, C.L. (2002). Nat. Rev. Cancer 2, 489–501.
Yap, T.A., Yan, L., Patnaik, A., Fearen, I., Olmos, D., Papadopoulos, K., Baird, R.D., Delgado, L.,
Taylor, A., Lupinacci, L., et al. (2011). J. Clin. Oncol. 29, 4688–4695. Yu, W.N., Nogueira, V., Sobhakumari, A., Patra, K.C., Bhaskar, P.T., and Hay, N. (2015). Cell Rep. 12, 610–621.
Defining and Targeting the Oncogenic Drivers of Neuroendocrine Prostate Cancer Brett S. Carver1,* 1Department of Surgery, Division of Urology, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA *Correspondence: [email protected] http://dx.doi.org/10.1016/j.ccell.2016.03.023
In this issue of Cancer Cell, Lee and colleagues (2016) 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 firstline management of metastatic prostate cancer, resulting in a delay in disease progression, although the vast majority of these tumors develop acquired castrateresistant 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., 2011; Scher et al., 2012). 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 ARindependent neuroendocrine (small-cell carcinoma) disease (Arora et al., 2013). 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., 2016). 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., 2016). 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 preclinical 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, Cancer Cell 29, April 11, 2016 431
Cancer Cell
Previews 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 castrateresistant 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. REFERENCES Arora, V.K., Schenkein, E., Murali, R., Subudhi, S.K., Wongvipat, J., Balbas, M.D., Shah, N., Cai,
L., Efstathiou, E., Logothetis, C., et al. (2013). Cell 155, 1309–1322. Beltran, H., Prandi, D., Mosquera, J.M., Benelli, M., Puca, L., Cyrta, J., Marotz, C., Giannopoulou, E., Chakravarthi, B.V., Varambally, S., et al. (2016). Nat. Med. 22, 298–305. de Bono, J.S., Logothetis, C.J., Molina, A., Fizazi, K., North, S., Chu, L., Chi, K.N., Jones, R.J., Goodman, O.B., Jr., Saad, F., et al.; COU-AA-301 Investigators (2011). N. Engl. J. Med. 364, 1995– 2005. Lee, 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. (2016). Cancer Cell 29, this issue, 536–547. Scher, 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 Investigators (2012). N. Engl. J. Med. 367, 1187– 1197.
Glycoholics Anonymous: Cancer Sobers Up with mTORC1 Vivian Fu,1 Toshiro Moroishi,1 and Kun-Liang Guan1,* 1Department of Pharmacology and Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA *Correspondence: [email protected] http://dx.doi.org/10.1016/j.ccell.2016.03.016
In this issue of Cancer Cell, Pusapati et al. (2016) reveal that mTORC1 orchestrates the metabolic reprogramming of cancer cells in response to glycolytic inhibitors, bypassing glycolysis by increasing glutamine uptake and pentose phosphate flux to generate energy and biomass. Cancer cells reprogram their metabolism to satisfy their heightened anabolic needs, exhibiting elevated rates of aerobic glycolysis, glutamine metabolism, and fatty acid synthesis (Vander Heiden et al., 2009). Notably, cancer cells consume about 10 times more glucose than normal cells and increase the rate of glycolysis by more than 30-fold to meet the bioenergetic requirements for their growth (Koppenol et al., 2011). Increased aerobic glycolysis is crucial not only for cellular energy but also for metabolic intermediates, which are necessary for macromolecular synthesis in malignant cells under nutrient-deficient conditions. Targeting metabolic processes such as glycolysis is an attractive therapeutic strategy; how432 Cancer Cell 29, April 11, 2016
ever, glycolytic inhibitors have been unsuccessful in the clinical setting. Drugs such as 2-Deoxy-Glucose (2-DG) demonstrate little to no effects on solid tumor growth, yet the mechanism for this is unclear (Maschek et al., 2004; Prasanna et al., 2009). In this issue, Pusapati et al. (2016) provide molecular insights into the mechanistic target of rapamycin complex 1 (mTORC1), which rewires the metabolic circuitry of cancer cells, permitting their escape from glycolysis dependency and thereby conferring resistance to glycolytic inhibitors such as 2-DG. Specifically, mTORC1 upregulates key components in carbon metabolism upon glycolytic inhibition, supplying alternate sources of glucose-derived carbons to the TCA cycle
and reducing equivalents for lipidogenesis (Figure 1). These new findings reveal an adaptive mechanism of cancer cells in response to glycolytic block and identify components of the mTORC1 pathway as potential therapeutic co-targets that may complement glycolytic inhibitors in cancer therapy. mTOR is a conserved kinase and is the catalytic subunit of mTORC1. mTORC1 is a master regulator of cell growth, promoting anabolic events such as protein synthesis and inhibiting catabolic events like autophagy (Jewell and Guan, 2013). The mTORC1 pathway integrates cues from nutrients, growth factors, energy, and stress, and these signals act in concert to produce both synergistic and
Previews Park, E.J., Lee, J.H., Yu, G.Y., He, G., Ali, S.R., Holzer, R.G., Osterreicher, C.H., Takahashi, H., and Karin, M. (2010). Cell 140, 197–208.
Wang, Q., Yu, W.-N., Chen, X., Peng, X.D., Jeon, S.-M., Birnbaum, M.J., Guzman, G., and Hay, N. (2016). Cancer Cell 29, this issue, 523–535.
Vivanco, I., and Sawyers, C.L. (2002). Nat. Rev. Cancer 2, 489–501.
Yap, T.A., Yan, L., Patnaik, A., Fearen, I., Olmos, D., Papadopoulos, K., Baird, R.D., Delgado, L.,
Taylor, A., Lupinacci, L., et al. (2011). J. Clin. Oncol. 29, 4688–4695. Yu, W.N., Nogueira, V., Sobhakumari, A., Patra, K.C., Bhaskar, P.T., and Hay, N. (2015). Cell Rep. 12, 610–621.
Defining and Targeting the Oncogenic Drivers of Neuroendocrine Prostate Cancer Brett S. Carver1,* 1Department of Surgery, Division of Urology, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA *Correspondence: [email protected] http://dx.doi.org/10.1016/j.ccell.2016.03.023
In this issue of Cancer Cell, Lee and colleagues (2016) 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 firstline management of metastatic prostate cancer, resulting in a delay in disease progression, although the vast majority of these tumors develop acquired castrateresistant 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., 2011; Scher et al., 2012). 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 ARindependent neuroendocrine (small-cell carcinoma) disease (Arora et al., 2013). 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., 2016). 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., 2016). 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 preclinical 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, Cancer Cell 29, April 11, 2016 431
Cancer Cell
Previews 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 castrateresistant 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. REFERENCES Arora, V.K., Schenkein, E., Murali, R., Subudhi, S.K., Wongvipat, J., Balbas, M.D., Shah, N., Cai,
L., Efstathiou, E., Logothetis, C., et al. (2013). Cell 155, 1309–1322. Beltran, H., Prandi, D., Mosquera, J.M., Benelli, M., Puca, L., Cyrta, J., Marotz, C., Giannopoulou, E., Chakravarthi, B.V., Varambally, S., et al. (2016). Nat. Med. 22, 298–305. de Bono, J.S., Logothetis, C.J., Molina, A., Fizazi, K., North, S., Chu, L., Chi, K.N., Jones, R.J., Goodman, O.B., Jr., Saad, F., et al.; COU-AA-301 Investigators (2011). N. Engl. J. Med. 364, 1995– 2005. Lee, 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. (2016). Cancer Cell 29, this issue, 536–547. Scher, 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 Investigators (2012). N. Engl. J. Med. 367, 1187– 1197.
Glycoholics Anonymous: Cancer Sobers Up with mTORC1 Vivian Fu,1 Toshiro Moroishi,1 and Kun-Liang Guan1,* 1Department of Pharmacology and Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA *Correspondence: [email protected] http://dx.doi.org/10.1016/j.ccell.2016.03.016
In this issue of Cancer Cell, Pusapati et al. (2016) reveal that mTORC1 orchestrates the metabolic reprogramming of cancer cells in response to glycolytic inhibitors, bypassing glycolysis by increasing glutamine uptake and pentose phosphate flux to generate energy and biomass. Cancer cells reprogram their metabolism to satisfy their heightened anabolic needs, exhibiting elevated rates of aerobic glycolysis, glutamine metabolism, and fatty acid synthesis (Vander Heiden et al., 2009). Notably, cancer cells consume about 10 times more glucose than normal cells and increase the rate of glycolysis by more than 30-fold to meet the bioenergetic requirements for their growth (Koppenol et al., 2011). Increased aerobic glycolysis is crucial not only for cellular energy but also for metabolic intermediates, which are necessary for macromolecular synthesis in malignant cells under nutrient-deficient conditions. Targeting metabolic processes such as glycolysis is an attractive therapeutic strategy; how432 Cancer Cell 29, April 11, 2016
ever, glycolytic inhibitors have been unsuccessful in the clinical setting. Drugs such as 2-Deoxy-Glucose (2-DG) demonstrate little to no effects on solid tumor growth, yet the mechanism for this is unclear (Maschek et al., 2004; Prasanna et al., 2009). In this issue, Pusapati et al. (2016) provide molecular insights into the mechanistic target of rapamycin complex 1 (mTORC1), which rewires the metabolic circuitry of cancer cells, permitting their escape from glycolysis dependency and thereby conferring resistance to glycolytic inhibitors such as 2-DG. Specifically, mTORC1 upregulates key components in carbon metabolism upon glycolytic inhibition, supplying alternate sources of glucose-derived carbons to the TCA cycle
and reducing equivalents for lipidogenesis (Figure 1). These new findings reveal an adaptive mechanism of cancer cells in response to glycolytic block and identify components of the mTORC1 pathway as potential therapeutic co-targets that may complement glycolytic inhibitors in cancer therapy. mTOR is a conserved kinase and is the catalytic subunit of mTORC1. mTORC1 is a master regulator of cell growth, promoting anabolic events such as protein synthesis and inhibiting catabolic events like autophagy (Jewell and Guan, 2013). The mTORC1 pathway integrates cues from nutrients, growth factors, energy, and stress, and these signals act in concert to produce both synergistic and