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  • Perspective
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Biology and evolution of poorly differentiated neuroendocrine tumors

Nature Medicine volume 23, pages 664–673 (2017)Cite this article

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Abstract

Neuroendocrine (NE) cancers are a diverse group of neoplasms typically diagnosed and treated on the basis of their site of origin. This Perspective focuses on advances in our understanding of the tumorigenesis and treatment of poorly differentiated neuroendocrine tumors. Recent evidence from sequencing indicates that, although neuroendocrine tumors can arise de novo, they can also develop as a result of lineage plasticity in response to pressure from targeted therapies. We discuss the shared genomic alterations of these tumors independently of their site of origin, and we explore potential therapeutic strategies on the basis of recent biological findings.

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Figure 1: Frequency and incidence.
Figure 2: Cell of origin of neuroblastomas and current model of NEPC arising following anti-AR therapy as a mechanism of resistance.
Figure 3: Examples of tumors referred to as 'neuroendocrine.'

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References

  1. Perren, A. et al. ENETS consensus guidelines for the standards of care in neuroendocrine tumors: pathology: diagnosis and prognostic stratification. Neuroendocrinology http://dx.doi.org/10.1159/000457956 (2017).

  2. Ferrone, C.R. et al. Determining prognosis in patients with pancreatic endocrine neoplasms: can the WHO classification system be simplified? J. Clin. Oncol. 25, 5609–5615 (2007).

    Article  PubMed  Google Scholar 

  3. Hochwald, S.N. et al. Prognostic factors in pancreatic endocrine neoplasms: an analysis of 136 cases with a proposal for low-grade and intermediate-grade groups. J. Clin. Oncol. 20, 2633–2642 (2002).

    Article  PubMed  Google Scholar 

  4. Liu, T.C., Hamilton, N., Hawkins, W., Gao, F. & Cao, D. Comparison of WHO Classifications (2004, 2010), the Hochwald grading system, and AJCC and ENETS staging systems in predicting prognosis in locoregional well-differentiated pancreatic neuroendocrine tumors. Am. J. Surg. Pathol. 37, 853–859 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  5. Tang, L.H. et al. Well-differentiated neuroendocrine tumors with a morphologically apparent high-grade component: a pathway distinct from poorly differentiated neuroendocrine carcinomas. Clin. Cancer Res. 22, 1011–1017 (2016).

    Article  CAS  PubMed  Google Scholar 

  6. den Bakker, M.A. & Thunnissen, F.B. Neuroendocrine tumours—challenges in the diagnosis and classification of pulmonary neuroendocrine tumours. J. Clin. Pathol. 66, 862–869 (2013).

    Article  CAS  PubMed  Google Scholar 

  7. Janson, E.T. et al. Nordic guidelines 2014 for diagnosis and treatment of gastroenteropancreatic neuroendocrine neoplasms. Acta Oncol. 53, 1284–1297 (2014).

    Article  PubMed  Google Scholar 

  8. Kidd, M., Modlin, I. & Öberg, K. Towards a new classification of gastroenteropancreatic neuroendocrine neoplasms. Nat. Rev. Clin. Oncol. 13, 691–705 (2016).

    Article  CAS  PubMed  Google Scholar 

  9. Priemer, D.S. et al. Neuroendocrine tumors of the prostate: emerging insights from molecular data and updates to the 2016 World Health Organization classification. Endocr. Pathol. 27, 123–135 (2016).

    Article  CAS  PubMed  Google Scholar 

  10. Reid, M.D., Balci, S., Saka, B. & Adsay, N.V. Neuroendocrine tumors of the pancreas: current concepts and controversies. Endocr. Pathol. 25, 65–79 (2014).

    Article  CAS  PubMed  Google Scholar 

  11. Rouzbahman, M. & Clarke, B. Neuroendocrine tumors of the gynecologic tract: select topics. Semin. Diagn. Pathol. 30, 224–233 (2013).

    Article  PubMed  Google Scholar 

  12. Scarpa, A. et al. Whole-genome landscape of pancreatic neuroendocrine tumours. Nature 543, 65–71 (2017).

    Article  CAS  PubMed  Google Scholar 

  13. Mollaoglu, G. et al. MYC drives progression of small cell lung cancer to a variant neuroendocrine subtype with vulnerability to aurora kinase inhibition. Cancer Cell 31, 270–285 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. George, J. et al. Comprehensive genomic profiles of small cell lung cancer. Nature 524, 47–53 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Fernandez-Cuesta, L. et al. Frequent mutations in chromatin-remodelling genes in pulmonary carcinoids. Nat. Commun. 5, 3518 (2014).

    Article  PubMed  CAS  Google Scholar 

  16. Rekhtman, N. et al. Next-generation sequencing of pulmonary large cell neuroendocrine carcinoma reveals small cell carcinoma-like and non-small cell carcinoma-like subsets. Clin. Cancer Res. 22, 3618–3629 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Peifer, M. et al. Integrative genome analyses identify key somatic driver mutations of small-cell lung cancer. Nat. Genet. 44, 1104–1110 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Beltran, H. et al. Divergent clonal evolution of castration-resistant neuroendocrine prostate cancer. Nat. Med. 22, 298–305 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Cancer Genome Atlas Research Network. Comprehensive molecular profiling of lung adenocarcinoma. Nature 511, 543–550 (2014).

  20. Ding, L. et al. Somatic mutations affect key pathways in lung adenocarcinoma. Nature 455, 1069–1075 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Imielinski, M. et al. Mapping the hallmarks of lung adenocarcinoma with massively parallel sequencing. Cell 150, 1107–1120 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Rizvi, N.A. et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 348, 124–128 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Tan, H.L. et al. Rb loss is characteristic of prostatic small cell neuroendocrine carcinoma. Clin. Cancer Res. 20, 890–903 (2014).

    Article  CAS  PubMed  Google Scholar 

  24. Feng, H., Shuda, M., Chang, Y. & Moore, P.S. Clonal integration of a polyomavirus in human Merkel cell carcinoma. Science 319, 1096–1100 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Berman-Booty, L.D. & Knudsen, K.E. Models of neuroendocrine prostate cancer. Endocr. Relat. Cancer 22, R33–R49 (2015).

    Article  CAS  PubMed  Google Scholar 

  26. Zhou, Z. et al. Synergy of p53 and Rb deficiency in a conditional mouse model for metastatic prostate cancer. Cancer Res. 66, 7889–7898 (2006).

    Article  CAS  PubMed  Google Scholar 

  27. Brodeur, G.M. & Castleberry, R.G. Neuroblastoma. in Principles and Practice of Pediatric Oncology (eds. Pizzo, P.A. & Poplack, D.G.) 739–767 (J.B. Lippincott Co., Philadelphia, PA, 1993).

    Google Scholar 

  28. Shuda, M. et al. Merkel cell polyomavirus small T antigen induces cancer and embryonic merkel cell proliferation in a transgenic mouse model. PLoS One 10, e0142329 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Spurgeon, M.E., Cheng, J., Bronson, R.T., Lambert, P.F. & DeCaprio, J.A. Tumorigenic activity of merkel cell polyomavirus T antigens expressed in the stratified epithelium of mice. Cancer Res. 75, 1068–1079 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Verhaegen, M.E. et al. Merkel cell polyomavirus small T antigen is oncogenic in transgenic mice. J. Invest. Dermatol. 135, 1415–1424 (2015).

    Article  CAS  PubMed  Google Scholar 

  31. Cavallaro, U., Niedermeyer, J., Fuxa, M. & Christofori, G. N-CAM modulates tumour-cell adhesion to matrix by inducing FGF-receptor signalling. Nat. Cell Biol. 3, 650–657 (2001).

    Article  CAS  PubMed  Google Scholar 

  32. Cui, M. et al. PTEN is a potent suppressor of small cell lung cancer. Mol. Cancer Res. 12, 654–659 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Kobayashi, S., Okada, S., Hasumi, T., Sato, N. & Fujimura, S. The significance of NSE and CEA as a differentiation marker for the cellular heterogeneity of small cell lung cancer. Tohoku J. Exp. Med. 189, 37–49 (1999).

    Article  CAS  PubMed  Google Scholar 

  34. McFadden, D.G. et al. Genetic and clonal dissection of murine small cell lung carcinoma progression by genome sequencing. Cell 156, 1298–1311 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Meuwissen, R. et al. Induction of small cell lung cancer by somatic inactivation of both Trp53 and Rb1 in a conditional mouse model. Cancer Cell 4, 181–189 (2003).

    Article  CAS  PubMed  Google Scholar 

  36. Schaffer, B.E. et al. Loss of p130 accelerates tumor development in a mouse model for human small-cell lung carcinoma. Cancer Res. 70, 3877–3883 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Shibayama, T. et al. Complementary roles of pro-gastrin-releasing peptide (ProGRP) and neuron specific enolase (NSE) in diagnosis and prognosis of small-cell lung cancer (SCLC). Lung Cancer 32, 61–69 (2001).

    Article  CAS  PubMed  Google Scholar 

  38. Borromeo, M.D. et al. ASCL1 and NEUROD1 reveal heterogeneity in pulmonary neuroendocrine tumors and regulate distinct genetic programs. Cell Rep. 16, 1259–1272 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Gazdar, A.F. et al. The comparative pathology of genetically engineered mouse models for neuroendocrine carcinomas of the lung. J. Thorac. Oncol. 10, 553–564 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. DeCaprio, J.A. et al. SV40 large tumor antigen forms a specific complex with the product of the retinoblastoma susceptibility gene. Cell 54, 275–283 (1988).

    Article  CAS  PubMed  Google Scholar 

  41. Lane, D.P. & Crawford, L.V. T antigen is bound to a host protein in SV40-transformed cells. Nature 278, 261–263 (1979).

    Article  CAS  PubMed  Google Scholar 

  42. Linzer, D.I. & Levine, A.J. Characterization of a 54K dalton cellular SV40 tumor antigen present in SV40-transformed cells and uninfected embryonal carcinoma cells. Cell 17, 43–52 (1979).

    Article  CAS  PubMed  Google Scholar 

  43. Gingrich, J.R., Barrios, R.J., Foster, B.A. & Greenberg, N.M. Pathologic progression of autochthonous prostate cancer in the TRAMP model. Prostate Cancer Prostatic Dis. 2, 70–75 (1999).

    Article  CAS  PubMed  Google Scholar 

  44. Gingrich, J.R. et al. Metastatic prostate cancer in a transgenic mouse. Cancer Res. 56, 4096–4102 (1996).

    CAS  PubMed  Google Scholar 

  45. Greenberg, N.M. et al. Prostate cancer in a transgenic mouse. Proc. Natl. Acad. Sci. USA 92, 3439–3443 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Kaplan-Lefko, P.J. et al. Pathobiology of autochthonous prostate cancer in a pre-clinical transgenic mouse model. Prostate 55, 219–237 (2003).

    Article  PubMed  Google Scholar 

  47. Duan, W. et al. Knockin of SV40 Tag oncogene in a mouse adenocarcinoma of the prostate model demonstrates advantageous features over the transgenic model. Oncogene 24, 1510–1524 (2005).

    Article  CAS  PubMed  Google Scholar 

  48. Gabril, M.Y. et al. A novel knock-in prostate cancer model demonstrates biology similar to that of human prostate cancer and suitable for preclinical studies. Mol. Ther. 11, 348–362 (2005).

    Article  CAS  PubMed  Google Scholar 

  49. Gabril, M.Y. et al. Prostate targeting: PSP94 gene promoter/enhancer region directed prostate tissue-specific expression in a transgenic mouse prostate cancer model. Gene Ther. 9, 1589–1599 (2002).

    Article  CAS  PubMed  Google Scholar 

  50. Garabedian, E.M., Humphrey, P.A. & Gordon, J.I. A transgenic mouse model of metastatic prostate cancer originating from neuroendocrine cells. Proc. Natl. Acad. Sci. USA 95, 15382–15387 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Klezovitch, O. et al. Hepsin promotes prostate cancer progression and metastasis. Cancer Cell 6, 185–195 (2004).

    Article  CAS  PubMed  Google Scholar 

  52. Kwabi-Addo, B. et al. Haploinsufficiency of the Pten tumor suppressor gene promotes prostate cancer progression. Proc. Natl. Acad. Sci. USA 98, 11563–11568 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Masumori, N. et al. A probasin-large T antigen transgenic mouse line develops prostate adenocarcinoma and neuroendocrine carcinoma with metastatic potential. Cancer Res. 61, 2239–2249 (2001).

    CAS  PubMed  Google Scholar 

  54. Perez-Stable, C. et al. Prostate, adrenocortical, and brown adipose tumors in fetal globin/T antigen transgenic mice. Lab. Invest. 74, 363–373 (1996).

    CAS  PubMed  Google Scholar 

  55. Berman-Booty, L.D. et al. Extra-prostatic transgene-associated neoplastic lesions in transgenic adenocarcinoma of the mouse prostate (TRAMP) mice. Toxicol. Pathol. 43, 186–197 (2015).

    Article  CAS  PubMed  Google Scholar 

  56. Suttie, A.W. et al. An investigation of the effects of late-onset dietary restriction on prostate cancer development in the TRAMP mouse. Toxicol. Pathol. 33, 386–397 (2005).

    Article  CAS  PubMed  Google Scholar 

  57. Tani, Y., Suttie, A., Flake, G.P., Nyska, A. & Maronpot, R.R. Epithelial-stromal tumor of the seminal vesicles in the transgenic adenocarcinoma mouse prostate model. Vet. Pathol. 42, 306–314 (2005).

    Article  CAS  PubMed  Google Scholar 

  58. Ku, S.Y. et al. Rb1 and Trp53 cooperate to suppress prostate cancer lineage plasticity, metastasis, and antiandrogen resistance. Science 355, 78–83 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Martin, P. et al. Prostate epithelial Pten/TP53 loss leads to transformation of multipotential progenitors and epithelial to mesenchymal transition. Am. J. Pathol. 179, 422–435 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Mu, P. et al. SOX2 promotes lineage plasticity and antiandrogen resistance in TP53- and RB1-deficient prostate cancer. Science 355, 84–88 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Brodeur, G.M. Neuroblastoma: biological insights into a clinical enigma. Nat. Rev. Cancer 3, 203–216 (2003).

    Article  CAS  PubMed  Google Scholar 

  62. Brodeur, G.M., Seeger, R.C., Schwab, M., Varmus, H.E. & Bishop, J.M. Amplification of N-myc in untreated human neuroblastomas correlates with advanced disease stage. Science 224, 1121–1124 (1984).

    Article  CAS  PubMed  Google Scholar 

  63. Kohl, N.E., Gee, C.E. & Alt, F.W. Activated expression of the N-myc gene in human neuroblastomas and related tumors. Science 226, 1335–1337 (1984).

    Article  CAS  PubMed  Google Scholar 

  64. Althoff, K. et al. A Cre-conditional MYCN-driven neuroblastoma mouse model as an improved tool for preclinical studies. Oncogene 34, 3357–3368 (2015).

    Article  CAS  PubMed  Google Scholar 

  65. Banerjee, S.A., Hoppe, P., Brilliant, M. & Chikaraishi, D.M. 5′ flanking sequences of the rat tyrosine hydroxylase gene target accurate tissue-specific, developmental, and transsynaptic expression in transgenic mice. J. Neurosci. 12, 4460–4467 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Nakamura, T. et al. Deletions and rearrangements of the retinoblastoma gene in hepatocellular carcinoma, insulinoma and some neurogenic tumors as found in a study of 121 tumors. Jpn. J. Clin. Oncol. 21, 325–329 (1991).

    CAS  PubMed  Google Scholar 

  67. The, I. et al. Neurofibromatosis type 1 gene mutations in neuroblastoma. Nat. Genet. 3, 62–66 (1993).

    Article  CAS  PubMed  Google Scholar 

  68. Weiss, W.A., Aldape, K., Mohapatra, G., Feuerstein, B.G. & Bishop, J.M. Targeted expression of MYCN causes neuroblastoma in transgenic mice. EMBO J. 16, 2985–2995 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Powers, J.T. et al. Multiple mechanisms disrupt the let-7 microRNA family in neuroblastoma. Nature 535, 246–251 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Dardenne, E. et al. N-Myc induces an EZH2-mediated transcriptional program driving neuroendocrine prostate cancer. Cancer Cell 30, 563–577 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Lee, J.K. et al. N-Myc drives neuroendocrine prostate cancer initiated from human prostate epithelial cells. Cancer Cell 29, 536–547 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Huijbers, I.J. et al. Rapid target gene validation in complex cancer mouse models using re-derived embryonic stem cells. EMBO Mol. Med. 6, 212–225 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Rudin, C.M. & Poirier, J.T. MYC, MAX, and small cell lung cancer. Cancer Discov. 4, 273–274 (2014).

    Article  CAS  PubMed  Google Scholar 

  74. Sos, M.L. et al. A framework for identification of actionable cancer genome dependencies in small cell lung cancer. Proc. Natl. Acad. Sci. USA 109, 17034–17039 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Teicher, B.A. Targets in small cell lung cancer. Biochem. Pharmacol. 87, 211–219 (2014).

    Article  CAS  PubMed  Google Scholar 

  76. Wistuba, I.I., Gazdar, A.F. & Minna, J.D. Molecular genetics of small cell lung carcinoma. Semin. Oncol. 28 (Suppl. 4), 3–13 (2001).

    Article  CAS  PubMed  Google Scholar 

  77. Kim, D.W. et al. Genetic requirement for Mycl and efficacy of RNA Pol I inhibition in mouse models of small cell lung cancer. Genes Dev. 30, 1289–1299 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Hofner, T. et al. Development and characteristics of preclinical experimental models for the research of rare neuroendocrine bladder cancer. J. Urol. 190, 2263–2270 (2013).

    Article  CAS  PubMed  Google Scholar 

  79. Kong-Beltran, M., Stamos, J. & Wickramasinghe, D. The Sema domain of Met is necessary for receptor dimerization and activation. Cancer Cell 6, 75–84 (2004).

    Article  CAS  PubMed  Google Scholar 

  80. Byers, L.A. et al. Proteomic profiling identifies dysregulated pathways in small cell lung cancer and novel therapeutic targets including PARP1. Cancer Discov. 2, 798–811 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Aryee, M.J. et al. DNA methylation alterations exhibit intraindividual stability and interindividual heterogeneity in prostate cancer metastases. Sci. Transl. Med. 5, 169ra10 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  82. Beltran, H. et al. Molecular characterization of neuroendocrine prostate cancer and identification of new drug targets. Cancer Discov. 1, 487–495 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Jelinic, P. et al. Recurrent SMARCA4 mutations in small cell carcinoma of the ovary. Nat. Genet. 46, 424–426 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Ramos, P. et al. Small cell carcinoma of the ovary, hypercalcemic type, displays frequent inactivating germline and somatic mutations in SMARCA4. Nat. Genet. 46, 427–429 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Poirier, J.T. et al. DNA methylation in small cell lung cancer defines distinct disease subtypes and correlates with high expression of EZH2. Oncogene 34, 5869–5878 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Pearse, A.G. The cytochemistry and ultrastructure of polypeptide hormone-producing cells of the APUD series and the embryologic, physiologic and pathologic implications of the concept. J. Histochem. Cytochem. 17, 303–313 (1969).

    Article  CAS  PubMed  Google Scholar 

  87. Fontaine, J. & Le Douarin, N.M. Analysis of endoderm formation in the avian blastoderm by the use of quail-chick chimaeras. The problem of the neurectodermal origin of the cells of the APUD series. J. Embryol. Exp. Morphol. 41, 209–222 (1977).

    CAS  PubMed  Google Scholar 

  88. Rosai, J. The origin of neuroendocrine tumors and the neural crest saga. Mod. Pathol. 24 (Suppl. 2), S53–S57 (2011).

    Article  CAS  PubMed  Google Scholar 

  89. Yachida, S. et al. Small cell and large cell neuroendocrine carcinomas of the pancreas are genetically similar and distinct from well-differentiated pancreatic neuroendocrine tumors. Am. J. Surg. Pathol. 36, 173–184 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  90. Brenner, B., Tang, L.H., Shia, J., Klimstra, D.S. & Kelsen, D.P. Small cell carcinomas of the gastrointestinal tract: clinicopathological features and treatment approach. Semin. Oncol. 34, 43–50 (2007).

    Article  CAS  PubMed  Google Scholar 

  91. Shia, J. et al. Is nonsmall cell type high-grade neuroendocrine carcinoma of the tubular gastrointestinal tract a distinct disease entity? Am. J. Surg. Pathol. 32, 719–731 (2008).

    Article  PubMed  Google Scholar 

  92. Oser, M.G., Niederst, M.J., Sequist, L.V. & Engelman, J.A. Transformation from non-small-cell lung cancer to small-cell lung cancer: molecular drivers and cells of origin. Lancet Oncol. 16, e165–e172 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Niederst, M.J. et al. RB loss in resistant EGFR mutant lung adenocarcinomas that transform to small-cell lung cancer. Nat. Commun. 6, 6377 (2015).

    Article  CAS  PubMed  Google Scholar 

  94. Sequist, L.V. et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci. Transl. Med. 3, 75ra26 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  95. Ohashi, K., Maruvka, Y.E., Michor, F. & Pao, W. Epidermal growth factor receptor tyrosine kinase inhibitor-resistant disease. J. Clin. Oncol. 31, 1070–1080 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Bean, J. et al. MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib. Proc. Natl. Acad. Sci. USA 104, 20932–20937 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Engelman, J.A. et al. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science 316, 1039–1043 (2007).

    Article  CAS  PubMed  Google Scholar 

  98. Kobayashi, S. et al. EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N. Engl. J. Med. 352, 786–792 (2005).

    Article  CAS  PubMed  Google Scholar 

  99. Epstein, J.I. et al. Proposed morphologic classification of prostate cancer with neuroendocrine differentiation. Am. J. Surg. Pathol. 38, 756–767 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  100. Lai, S.L. et al. Molecular genetic characterization of neuroendocrine lung cancer cell lines. Anticancer Res. 15, 225–232 (1995).

    CAS  PubMed  Google Scholar 

  101. Mertz, K.D. et al. Molecular characterization of TMPRSS2-ERG gene fusion in the NCI-H660 prostate cancer cell line: a new perspective for an old model. Neoplasia 9, 200–206 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Burchardt, T. et al. Transdifferentiation of prostate cancer cells to a neuroendocrine cell phenotype in vitro and in vivo. J. Urol. 162, 1800–1805 (1999).

    Article  CAS  PubMed  Google Scholar 

  103. Bang, Y.J. et al. Terminal neuroendocrine differentiation of human prostate carcinoma cells in response to increased intracellular cyclic AMP. Proc. Natl. Acad. Sci. USA 91, 5330–5334 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Qiu, Y., Robinson, D., Pretlow, T.G. & Kung, H.J. Etk/Bmx, a tyrosine kinase with a pleckstrin-homology domain, is an effector of phosphatidylinositol 3′-kinase and is involved in interleukin 6-induced neuroendocrine differentiation of prostate cancer cells. Proc. Natl. Acad. Sci. USA 95, 3644–3649 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Deng, X. et al. Ionizing radiation induces prostate cancer neuroendocrine differentiation through interplay of CREB and ATF2: implications for disease progression. Cancer Res. 68, 9663–9670 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Lin, D. et al. High fidelity patient-derived xenografts for accelerating prostate cancer discovery and drug development. Cancer Res. 74, 1272–1283 (2014).

    Article  CAS  PubMed  Google Scholar 

  107. True, L.D. et al. A neuroendocrine/small cell prostate carcinoma xenograft-LuCaP 49. Am. J. Pathol. 161, 705–715 (2002).

    Article  PubMed  PubMed Central  Google Scholar 

  108. van Haaften Day, C. et al. Xenografted small cell undifferentiated cancer of prostate: possible common origin with prostatic adenocarcinoma. Prostate 11, 271–279 (1987).

    Article  CAS  PubMed  Google Scholar 

  109. Pinthus, J.H. et al. WISH-PC2: a unique xenograft model of human prostatic small cell carcinoma. Cancer Res. 60, 6563–6567 (2000).

    CAS  PubMed  Google Scholar 

  110. Lapuk, A.V. et al. From sequence to molecular pathology, and a mechanism driving the neuroendocrine phenotype in prostate cancer. J. Pathol. 227, 286–297 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Akamatsu, S. et al. The placental gene PEG10 promotes progression of neuroendocrine prostate cancer. Cell Reports 12, 922–936 (2015).

    Article  CAS  PubMed  Google Scholar 

  112. Aparicio, A. et al. Neuroendocrine prostate cancer xenografts with large-cell and small-cell features derived from a single patient's tumor: morphological, immunohistochemical, and gene expression profiles. Prostate 71, 846–856 (2011).

    Article  CAS  PubMed  Google Scholar 

  113. Noordzij, M.A. et al. Neuroendocrine differentiation in human prostatic tumor models. Am. J. Pathol. 149, 859–871 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Huss, W.J., Gregory, C.W. & Smith, G.J. Neuroendocrine cell differentiation in the CWR22 human prostate cancer xenograft: association with tumor cell proliferation prior to recurrence. Prostate 60, 91–97 (2004).

    Article  PubMed  Google Scholar 

  115. Chen, H. et al. Pathogenesis of prostatic small cell carcinoma involves the inactivation of the P53 pathway. Endocr. Relat. Cancer 19, 321–331 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Kareta, M.S. et al. Inhibition of pluripotency networks by the Rb tumor suppressor restricts reprogramming and tumorigenesis. Cell Stem Cell 16, 39–50 (2015).

    Article  CAS  PubMed  Google Scholar 

  117. Bishop, J.L. et al. The master neural transcription factor BRN2 is an androgen receptor-suppressed driver of neuroendocrine differentiation in prostate cancer. Cancer Discov. 7, 54–71 (2017).

    Article  CAS  PubMed  Google Scholar 

  118. Zou, M. et al. Transdifferentiation as a mechanism of treatment resistance in a mouse model of castration-resistant prostate cancer. Cancer Discov. http://dx.doi.org/10.1158/2159-8290.CD-16-1174 (2017).

  119. Lynch, T.J. et al. Ipilimumab in combination with paclitaxel and carboplatin as first-line treatment in stage IIIB/IV non-small-cell lung cancer: results from a randomized, double-blind, multicenter phase II study. J. Clin. Oncol. 30, 2046–2054 (2012).

    Article  CAS  PubMed  Google Scholar 

  120. Nghiem, P.T. et al. PD-1 blockade with pembrolizumab in advanced Merkel-cell carcinoma. N. Engl. J. Med. 374, 2542–2552 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Khoo, K.H., Verma, C.S. & Lane, D.P. Drugging the p53 pathway: understanding the route to clinical efficacy. Nat. Rev. Drug Discov. 13, 217–236 (2014).

    Article  CAS  PubMed  Google Scholar 

  122. Mantovani, F., Walerych, D. & Sal, G.D. Targeting mutant p53 in cancer: a long road to precision therapy. FEBS J. 284, 837–850 (2017).

    Article  CAS  PubMed  Google Scholar 

  123. Brockmann, M. et al. Small molecule inhibitors of aurora-a induce proteasomal degradation of N-myc in childhood neuroblastoma. Cancer Cell 24, 75–89 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Gustafson, W.C. et al. Drugging MYCN through an allosteric transition in Aurora kinase A. Cancer Cell 26, 414–427 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Hook, K.E. et al. An integrated genomic approach to identify predictive biomarkers of response to the aurora kinase inhibitor PF-03814735. Mol. Cancer Ther. 11, 710–719 (2012).

    Article  CAS  PubMed  Google Scholar 

  126. Jahchan, N.S. et al. Identification and targeting of long-term tumor-propagating cells in small cell lung cancer. Cell Rep. 16, 644–656 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Baca, S.C. et al. Punctuated evolution of prostate cancer genomes. Cell 153, 666–677 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Bailey, P. et al. Genomic analyses identify molecular subtypes of pancreatic cancer. Nature 531, 47–52 (2016).

    Article  CAS  PubMed  Google Scholar 

  129. Barbieri, C.E. et al. Exome sequencing identifies recurrent SPOP, FOXA1 and MED12 mutations in prostate cancer. Nat. Genet. 44, 685–689 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Biankin, A.V. et al. Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes. Nature 491, 399–405 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Cancer Genome Atlas Research Network. The molecular taxonomy of primary prostate cancer. Cell 163, 1011–1025 (2015).

  132. Grasso, C.S. et al. The mutational landscape of lethal castration-resistant prostate cancer. Nature 487, 239–243 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Kumar, A. et al. Substantial interindividual and limited intraindividual genomic diversity among tumors from men with metastatic prostate cancer. Nat. Med. 22, 369–378 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Rudin, C.M. et al. Comprehensive genomic analysis identifies SOX2 as a frequently amplified gene in small-cell lung cancer. Nat. Genet. 44, 1111–1116 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Taylor, B.S. et al. Integrative genomic profiling of human prostate cancer. Cancer Cell 18, 11–22 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Marshall, G.M. et al. The prenatal origins of cancer. Nat. Rev. Cancer 14, 277–289 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Zimmerman, K.A. et al. Differential expression of myc family genes during murine development. Nature 319, 780–783 (1986).

    Article  CAS  PubMed  Google Scholar 

  138. Yuan, J. & Yankner, B.A. Apoptosis in the nervous system. Nature 407, 802–809 (2000).

    Article  CAS  PubMed  Google Scholar 

  139. Kelly, K. & Balk, S.P. Reprogramming to resist. Science 355, 29–30 (2017).

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Caryl and Israel Englander Institute for Precision Medicine, New York Presbyterian Hospital–Weill Cornell Medicine, New York, New York, USA

    David S Rickman, Himisha Beltran, Francesca Demichelis & Mark A Rubin

  2. Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, New York, USA

    David S Rickman & Mark A Rubin

  3. Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, New York, USA

    David S Rickman, Himisha Beltran & Mark A Rubin

  4. Department of Medicine, Division Medical Oncology, Weill Cornell Medicine, New York, New York, USA

    Himisha Beltran

  5. Institute for Computational Biomedicine, Weill Cornell Medicine, New York, New York, USA

    Francesca Demichelis

  6. Centre for Integrative Biology, University of Trento, Trento, Italy

    Francesca Demichelis

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  1. David S Rickman
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  2. Himisha Beltran
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Correspondence to Mark A Rubin.

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Competing interests

M.A.R., F.D., H.B. and D.S.R. have filed patent applications in the area of biomarkers and treatment for neuroendocrine prostate cancer. M.A.R., H.B. and D.S.R. have a sponsored research agreement in the area of neuroendocrine prostate cancer with Janssen Pharma.

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Rickman, D., Beltran, H., Demichelis, F. et al. Biology and evolution of poorly differentiated neuroendocrine tumors. Nat Med 23, 664–673 (2017). https://doi.org/10.1038/nm.4341

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