Small-cell lung cancer: what we know, what we need to know and the path forward

Article metrics

  • A Corrigendum to this article was published on 10 November 2017

Key Points

  • Small-cell lung cancer (SCLC) is a deadly cancer associated with smoke exposure that has neuroendocrine (NE) cell properties and is pathologically, molecularly, biologically and clinically very different from other lung cancers.

  • While most patients with SCLC respond initially to cytotoxic therapy, almost all tumours recur and are resistant to further therapy. The mortality is very high, resulting in SCLC being designated as a recalcitrant cancer.

  • As tumours in patients with SCLC are seldom resected, tumour materials for research are scant, resulting in a major barrier for translational research.

  • The initiating molecular events are believed to be inactivation of TP53 and RB1, which mainly occurs in NE cells in the respiratory epithelium, although many other genes and signalling pathways are disrupted, especially Notch signalling.

  • For the past 30 years, there have been no important clinical developments or approved, effective conventional or targeted therapies for SCLC. There are no effective methods for early detection or prevention (other than smoking avoidance).

  • However, recently there has been an awakening of interest and funding, resulting in the identification of many promising therapeutic approaches, some of which are already in clinical trials. Thus, while the past has been bleak, the future offers greater promise.

Abstract

Small-cell lung cancer (SCLC) is a deadly tumour accounting for approximately 15% of lung cancers and is pathologically, molecularly, biologically and clinically very different from other lung cancers. While the majority of tumours express a neuroendocrine programme (integrating neural and endocrine properties), an important subset of tumours have low or absent expression of this programme. The probable initiating molecular events are inactivation of TP53 and RB1, as well as frequent disruption of several signalling networks, including Notch signalling. SCLC, when diagnosed, is usually widely metastatic and initially responds to cytotoxic therapy but nearly always rapidly relapses with resistance to further therapies. There were no important therapeutic clinical advances for 30 years, leading SCLC to be designated a 'recalcitrant cancer'. Scientific studies are hampered by a lack of tissue availability. However, over the past 5 years, there has been a worldwide resurgence of studies on SCLC, including comprehensive molecular analyses, the development of relevant genetically engineered mouse models and the establishment of patient-derived xenografts. These studies have led to the discovery of new potential therapeutic vulnerabilities for SCLC and therefore to new clinical trials. Thus, while the past has been bleak, the future offers greater promise.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Timeline of SCLC through the Ages.
Figure 2: Multistage pathogenesis of SCLC.
Figure 3: Notch signalling and its role in SCLC.
Figure 4: Epigenetic regulation in SCLC.

Change history

  • 10 November 2017

    in the section 'DNA methylation and EZH2' - second to last sentence (starting 'EZH2 overexpression promoted SCLC progression…') - please change the sentence to read 'EZH2 overexpression promoted SCLC progression by suppressing the transforming growth factor-β (TGFβ)-SMAD pathway via methylation, which in turn results in loss of suppression of ASCL1 (REF. 92).' In the section 'Chromatin modifiers' - sentence starting 'EZH2 plays a major role in SCLC via several mechanisms…' - please change the sentence to read: 'EZH2 plays a major role in SCLC via several mechanisms, including maintenance of stem cells, suppression of apoptosis, increased cell proliferation, activation of ASCL1 expression (via suppression of TGFβ signalling) and induction of chemoresistance (via suppression of SLFN11)92,102–104, making EZH2 targeting a major cancer therapy priority97,105.'

References

  1. 1

    American Cancer Society. Global Cancer Facts & Figures 3rd edn (American Cancer Society, 2015).

  2. 2

    Rudin, C. M. & Poirier, J. T. Small-cell lung cancer in 2016: shining light on novel targets and therapies. Nat. Rev. Clin. Oncol. 14, 75–76 (2017).

  3. 3

    Alexandrov, L. B. et al. Mutational signatures associated with tobacco smoking in human cancer. Science 354, 618–622 (2016). This reference describes that smoking is associated with an increased mutation burden and with multiple distinct mutational signatures.

  4. 4

    George, J. et al. Comprehensive genomic profiles of small cell lung cancer. Nature 524, 47–53 (2015). This is the most comprehensive report of the genomic profiling of SCLC to date.

  5. 5

    Bunn, P. A. Jr et al. Small cell lung cancer: can recent advances in biology and molecular biology be translated into improved outcomes? J. Thorac Oncol. 11, 453–474 (2016). This article is an excellent summary of the data presented at an international meeting on SCLC.

  6. 6

    Kawahara, M. et al. Second primary tumours in more than 2-year disease-free survivors of small-cell lung cancer in Japan: the role of smoking cessation. Br. J. Cancer 78, 409–412 (1998).

  7. 7

    Torre, L. A., Siegel, R. L. & Jemal, A. Lung cancer statistics. Adv. Exp. Med. Biol. 893, 1–19 (2016).

  8. 8

    Cancer Research UK. Lung cancer incidence statistics. Cancer Research UK http://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/lung-cancer/incidence (2014).

  9. 9

    Liu, J., Cheng, Y., Li, H. & Zhang, S. Current status of small cell lung cancer in China. J. Cancer Biol. Res. 2, 1032 (2014).

  10. 10

    Lewis, D. R., Check, D. P., Caporaso, N. E., Travis, W. D. & Devesa, S. S. US lung cancer trends by histologic type. Cancer 120, 2883–2892 (2014).

  11. 11

    Park, J. Y. & Jang, S. H. Epidemiology of Lung cancer in Korea: recent trends. Tuberc Respir. Dis. 79, 58–69 (2016).

  12. 12

    Govindan, R. et al. Changing epidemiology of small-cell lung cancer in the United States over the last 30 years: analysis of the surveillance, epidemiologic, and end results database. J. Clin. Oncol. 24, 4539–4544 (2006).

  13. 13

    US Congress. H.R.733 — Recalcitrant Cancer Research Act of 2012. Congress.gov https://www.congress.gov/bill/112th-congress/house-bill/733 (2012). The US Congress declares that SCLC is a recalcitrant cancer requiring special resources and efforts.

  14. 14

    Barnard, W. The nature of the “oat celled” sarcoma of the mediastinum. J. Pathol. Bacteriol. 29, 241–244 (1926). This study represents the identification of SCLC as a lung cancer.

  15. 15

    Azzopardi, J. G. Oat-cell carcinoma of the bronchus. J. Pathol. Bacteriol. 78, 513–519 (1959). This is the first detailed description of the pathology of SCLC and the recognition that it is a distinct form of lung cancer.

  16. 16

    Wong, Y. N., Jack, R. H., Mak, V., Henrik, M. & Davies, E. A. The epidemiology and survival of extrapulmonary small cell carcinoma in South East England, 1970–2004. BMC Cancer 9, 209 (2009).

  17. 17

    Matthews, M. J., Kanhouwa, S., Pickren, J. & Robinette, D. Frequency of residual and metastatic tumor in patients undergoing curative surgical resection for lung cancer. Cancer Chemother. Rep. 3 4, 63–67 (1973). This is a seminal report indicating that SCLC is usually metastatic at the time of diagnosis.

  18. 18

    Bensch, K. G., Corrin, B., Pariente, R. & Spencer, H. Oat-cell carcinoma of the lung. Its origin and relationship to bronchial carcinoid. Cancer 22, 1163–1172 (1968).

  19. 19

    Pearse, A. G. 5-Hydroxytryptophan uptake by dog thyroid 'C' cells, and its possible significance in polypeptide hormone production. Nature 211, 598–600 (1966).

  20. 20

    Pearse, A. G. The diffuse neuroendocrine system: peptides, amines, placodes and the APUD theory. Prog. Brain Res. 68, 25–31 (1986).

  21. 21

    Baylin, S. B. “APUD” cells: fact and fiction. Trends Endocrinol. Metab. 1, 198–204 (1990).

  22. 22

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

  23. 23

    Gazdar, A. F. et al. Establishment of continuous, clonable cultures of small-cell carcinoma of lung which have amine precursor uptake and decarboxylation cell properties. Cancer Res. 40, 3502–3507 (1980).

  24. 24

    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).

  25. 25

    Borges, M. et al. An achaete-scute homologue essential for neuroendocrine differentiation in the lung. Nature 386, 852–855 (1997). This is the first report of ASCL1 being present in SCLC and its link to NE cell properties.

  26. 26

    Vasconcelos, F. F. & Castro, D. S. Transcriptional control of vertebrate neurogenesis by the proneural factor Ascl1. Front. Cell. Neurosci. 8, 412 (2014).

  27. 27

    Augustyn, A. et al. ASCL1 is a lineage oncogene providing therapeutic targets for high-grade neuroendocrine lung cancers. Proc. Natl Acad. Sci. USA 111, 14788–14793 (2014).

  28. 28

    Lim, J. S. et al. Intratumoural heterogeneity generated by Notch signalling promotes small-cell lung cancer. Nature 545, 360–364 (2017).

  29. 29

    Carney, D. N. et al. Establishment and identification of small cell lung cancer cell lines having classic and variant features. Cancer Res. 45, 2913–2923 (1985).

  30. 30

    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). This study reports the finding that in a Myc -driven GEMM, Ascl1 -driven 'classic' tumours can switch to Neurod1 -driven 'variant' forms.

  31. 31

    La Rosa, S. et al. TTF1 expression in normal lung neuroendocrine cells and related tumors: immunohistochemical study comparing two different monoclonal antibodies. Virchows Arch. 457, 497–507 (2010).

  32. 32

    Yamaguchi, T., Hosono, Y., Yanagisawa, K. & Takahashi, T. NKX2-1/TTF-1: an enigmatic oncogene that functions as a double-edged sword for cancer cell survival and progression. Cancer Cell 23, 718–723 (2013).

  33. 33

    Rudin, C. M. et al. Treatment of small-cell lung cancer: American Society of Clinical Oncology endorsement of the American College of Chest Physicians guideline. J. Clin. Oncol. 33, 4106–4111 (2015).

  34. 34

    Gazdar, A. F., Carney, D. N., Nau, M. M. & Minna, J. D. Characterization of variant subclasses of cell lines derived from small cell lung cancer having distinctive biochemical, morphological, and growth properties. Cancer Res. 45, 2924–2930 (1985).

  35. 35

    Brennan, J. et al. myc family DNA amplification in 107 tumors and tumor cell lines from patients with small cell lung cancer treated with different combination chemotherapy regimens. Cancer Res. 51, 1708–1712 (1991).

  36. 36

    Carney, D. N., Mitchell, J. B. & Kinsella, T. J. In vitro radiation and chemotherapy sensitivity of established cell lines of human small cell lung cancer and its large cell morphological variants. Cancer Res. 43, 2806–2811 (1983).

  37. 37

    Poirier, J. T. et al. Selective tropism of Seneca Valley virus for variant subtype small cell lung cancer. J. Natl Cancer Inst. 105, 1059–1065 (2013).

  38. 38

    Johnson, B. E. et al. MYC family DNA amplification in 126 tumor cell lines from patients with small cell lung cancer. J. Cell. Biochem. Suppl. 24, 210–217 (1996). This is a report indicating that MYC family members are often amplified in SCLC tumours and cell lines.

  39. 39

    Calbo, J. et al. A functional role for tumor cell heterogeneity in a mouse model of small cell lung cancer. Cancer Cell 19, 244–256 (2011).

  40. 40

    Takebe, N. et al. Targeting Notch, Hedgehog, and Wnt pathways in cancer stem cells: clinical update. Nat. Rev. Clin. Oncol. 12, 445–464 (2015).

  41. 41

    Codony-Servat, J., Verlicchi, A. & Rosell, R. Cancer stem cells in small cell lung cancer. Transl Lung Cancer Res. 5, 16–25 (2016).

  42. 42

    Sullivan, J. P., Minna, J. D. & Shay, J. W. Evidence for self-renewing lung cancer stem cells and their implications in tumor initiation, progression, and targeted therapy. Cancer Metastasis Rev. 29, 61–72 (2010).

  43. 43

    Semenova, E. A., Nagel, R. & Berns, A. Origins, genetic landscape, and emerging therapies of small cell lung cancer. Genes Dev. 29, 1447–1462 (2015).

  44. 44

    Zhang, S. & Cui, W. Sox2, a key factor in the regulation of pluripotency and neural differentiation. World J. Stem Cells 6, 305–311 (2014).

  45. 45

    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).

  46. 46

    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).

  47. 47

    Subramanian, J. & Govindan, R. Small cell, big problem! Stem cells, root cause? Clin. Lung Cancer 9, 252–253 (2008).

  48. 48

    Travis, W. D., Brambilla, E., Burke, A. P., Marx, A., & Nicholson, A. G. WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart (IARC Press, 2015). This is the latest WHO (World Health Organization) pathological classification of SCLC.

  49. 49

    Shekhani, M. T., Jayanthy, A. S., Maddodi, N. & Setaluri, V. Cancer stem cells and tumor transdifferentiation: implications for novel therapeutic strategies. Am. J. Stem Cells 2, 52–61 (2013).

  50. 50

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

  51. 51

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

  52. 52

    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).

  53. 53

    Wistuba, I. I. et al. Molecular changes in the bronchial epithelium of patients with small cell lung cancer. Clin. Cancer Res. 6, 2604–2610 (2000). This is a report indicating the very large number of molecular changes occurring in the non-neoplastic respiratory epithelium in the lungs of patients with SCLC.

  54. 54

    Alexandrov, L. B. et al. Signatures of mutational processes in human cancer. Nature 500, 415–421 (2013).

  55. 55

    Pleasance, E. D. et al. A small-cell lung cancer genome with complex signatures of tobacco exposure. Nature 463, 184–190 (2010). This study reports the first sequencing of an SCLC sample, indicating the very large number of mutational events present in SCLC cells.

  56. 56

    Govindan, R. et al. Genomic landscape of non-small cell lung cancer in smokers and never-smokers. Cell 150, 1121–1134 (2012).

  57. 57

    Roberts, S. A. et al. An APOBEC cytidine deaminase mutagenesis pattern is widespread in human cancers. Nat. Genet. 45, 970–976 (2013).

  58. 58

    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). The authors describe the first 'double knockout' model for a GEMM for SCLC.

  59. 59

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

  60. 60

    Kwon, M. C. & Berns, A. Mouse models for lung cancer. Mol. Oncol. 7, 165–177 (2013).

  61. 61

    Whang-Peng, J. et al. Specific chromosome defect associated with human small-cell lung cancer; deletion 3p(14–23). Science 215, 181–182 (1982). The finding that most SCLC cells contain extensive deletions of the short arm of chromosome 3 is first reported in this article.

  62. 62

    Wistuba, I. I. et al. High resolution chromosome 3p allelotyping of human lung cancer and preneoplastic/preinvasive bronchial epithelium reveals multiple, discontinuous sites of 3p allele loss and three regions of frequent breakpoints. Cancer Res. 60, 1949–1960 (2000).

  63. 63

    ter Elst, A. et al. Functional analysis of lung tumor suppressor activity at 3p21.3. Genes Chromosomes Cancer 45, 1077–1093 (2006).

  64. 64

    Zabarovsky, E. R., Lerman, M. I. & Minna, J. D. Tumor suppressor genes on chromosome 3p involved in the pathogenesis of lung and other cancers. Oncogene 21, 6915–6935 (2002).

  65. 65

    Sozzi, G., Huebner, K. & Croce, C. M. Fhit in human cancer. Adv. Cancer Res. 74, 141–166 (1998).

  66. 66

    Varella-Garcia, M. Chromosomal and genomic changes in lung cancer. Cell Adh. Migr. 4, 100–106 (2010).

  67. 67

    Lerman, M. I. & Minna, J. D. The 630-kb lung cancer homozygous deletion region on human chromosome 3p21.3: identification and evaluation of the resident candidate tumor suppressor genes. Cancer Res. 60, 6116–6133 (2000).

  68. 68

    Durkin, S. G. & Glover, T. W. Chromosome fragile sites. Annu. Rev. Genet. 41, 169–192 (2007).

  69. 69

    Sekido, Y. et al. Molecular analysis of the von Hippel-Lindau disease tumor suppressor gene in human lung cancer cell lines. Oncogene 9, 1599–1604 (1994).

  70. 70

    Meder, L. et al. NOTCH, ASCL1, p53 and RB alterations define an alternative pathway driving neuroendocrine and small cell lung carcinomas. Int. J. Cancer 138, 927–938 (2016).

  71. 71

    Saunders, L. R. et al. A DLL3-targeted antibody-drug conjugate eradicates high-grade pulmonary neuroendocrine tumor-initiating cells in vivo. Sci. Transl Med. 7, 302ra136 (2015).

  72. 72

    Ntziachristos, P., Lim, J. S., Sage, J. & Aifantis, I. From fly wings to targeted cancer therapies: a centennial for notch signaling. Cancer Cell 25, 318–334 (2014).

  73. 73

    Dylla, S. J. Toppling high-grade pulmonary neuroendocrine tumors with a DLL3-targeted trojan horse. Mol. Cell. Oncol. 3, e1101515 (2016).

  74. 74

    Little, C. D., Nau, M. M., Carney, D. N., Gazdar, A. F. & Minna, J. D. Amplification and expression of the c-myc oncogene in human lung cancer cell lines. Nature 306, 194–196 (1983).

  75. 75

    Nau, M. M. et al. L-Myc, a new myc-related gene amplified and expressed in human small cell lung cancer. Nature 318, 69–73 (1985). This report describes the cloning of MYCL from an SCLC cell line.

  76. 76

    Johnson, B. E., Brennan, J. F., Ihde, D. C. & Gazdar, A. F. myc family DNA amplification in tumors and tumor cell lines from patients with small-cell lung cancer. J. Natl Cancer Inst. Monogr. (13), 39–43 (1992).

  77. 77

    Alves Rde, C., Meurer, R. T. & Roehe, A. V. MYC amplification is associated with poor survival in small cell lung cancer: a chromogenic in situ hybridization study. J. Cancer Res. Clin. Oncol. 140, 2021–2025 (2014).

  78. 78

    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).

  79. 79

    Fiorentino, F. P. et al. Growth suppression by MYC inhibition in small cell lung cancer cells with TP53 and RB1 inactivation. Oncotarget 7, 31014–31028 (2016).

  80. 80

    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).

  81. 81

    Helfrich, B. A. et al. Barasertib (AZD1152), a small molecule Aurora B Inhibitor, inhibits the growth of SCLC cell lines in vitro and in vivo. Mol. Cancer Ther. 15, 2314–2322 (2016). This report finds that Aurora kinase inhibitors inhibit the growth of SCLC cell lines with MYC family amplification, offering a promising therapeutic approach.

  82. 82

    Romero, O. A. et al. MAX inactivation in small cell lung cancer disrupts MYC-SWI/SNF programs and is synthetic lethal with BRG1. Cancer Discov. 4, 292–303 (2014).

  83. 83

    Shibata, T., Kokubu, A., Tsuta, K. & Hirohashi, S. Oncogenic mutation of PIK3CA in small cell lung carcinoma: a potential therapeutic target pathway for chemotherapy-resistant lung cancer. Cancer Lett. 283, 203–211 (2009).

  84. 84

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

  85. 85

    Wynes, M. W. et al. FGFR1 mRNA and protein expression, not gene copy number, predict FGFR TKI sensitivity across all lung cancer histologies. Clin. Cancer Res. 20, 3299–3309 (2014).

  86. 86

    Schultheis, A. M. et al. Fibroblast growth factor receptor 1 (FGFR1) amplification is a potential therapeutic target in small-cell lung cancer. Mod. Pathol. 27, 214–221 (2014).

  87. 87

    Cristea, S. & Sage, J. Is the canonical RAF/MEK/ERK signaling pathway a therapeutic target in SCLC? J. Thorac Oncol. 11, 1233–1241 (2016).

  88. 88

    Jones, P. A., Issa, J. P. & Baylin, S. Targeting the cancer epigenome for therapy. Nat. Rev. Genet. 17, 630–641 (2016).

  89. 89

    Kazanets, A., Shorstova, T., Hilmi, K., Marques, M. & Witcher, M. Epigenetic silencing of tumor suppressor genes: paradigms, puzzles, and potential. Biochim. Biophys. Acta 1865, 275–288 (2016).

  90. 90

    Kalari, S., Jung, M., Kernstine, K. H., Takahashi, T. & Pfeifer, G. P. The DNA methylation landscape of small cell lung cancer suggests a differentiation defect of neuroendocrine cells. Oncogene 32, 3559–3568 (2013).

  91. 91

    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).

  92. 92

    Murai, F. et al. EZH2 promotes progression of small cell lung cancer by suppressing the TGF-ß-Smad-ASCL1 pathway. Cell Discov. 1, 15026 (2015).

  93. 93

    Agathanggelou, A. et al. Methylation associated inactivation of RASSF1A from region 3p21.3 in lung, breast and ovarian tumours. Oncogene 20, 1509–1518. (2001).

  94. 94

    Burbee, D. G. et al. Epigenetic inactivation of RASSF1A in lung and breast cancers and malignant phenotype suppression. J. Natl Cancer Inst. 93, 691–699 (2001).

  95. 95

    Simon, J. A. & Lange, C. A. Roles of the EZH2 histone methyltransferase in cancer epigenetics. Mutat. Res. 647, 21–29 (2008).

  96. 96

    Jiang, T. et al. Prognostic value of high EZH2 expression in patients with different types of cancer: a systematic review with meta-analysis. Oncotarget 7, 4584–4597 (2016).

  97. 97

    Kim, K. H. & Roberts, C. W. Targeting EZH2 in cancer. Nat. Med. 22, 128–134 (2016).

  98. 98

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

  99. 99

    Augert, A. et al. Small cell lung cancer exhibits frequent inactivating mutations in the histone methyltransferase KMT2D/MLL2: CALGB 151111 (Alliance). J. Thorac Oncol. 12, 704–713 (2017).

  100. 100

    Kaur, G. et al. Bromodomain and hedgehog pathway targets in small cell lung cancer. Cancer Lett. 371, 225–239 (2016). The authors of this study report that bromodomain inhibitors inhibit the growth of SCLC cell lines, especially those with high expression of MYC family members.

  101. 101

    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).

  102. 102

    Gardner, E. E. et al. Chemosensitive relapse in small cell lung cancer proceeds through an EZH2-SLFN11 axis. Cancer Cell 31, 286–299 (2017).

  103. 103

    Hubaux, R. et al. EZH2 promotes E2F-driven SCLC tumorigenesis through modulation of apoptosis and cell-cycle regulation. J. Thorac Oncol. 8, 1102–1106 (2013).

  104. 104

    Wen, Y., Cai, J., Hou, Y., Huang, Z. & Wang, Z. Role of EZH2 in cancer stem cells: from biological insight to a therapeutic target. Oncotarget 8, 37974–37990 (2017).

  105. 105

    Frankel, A. E., Liu, X. & Minna, J. D. Developing EZH2-targeted therapy for lung cancer. Cancer Discov. 6, 949–952 (2016).

  106. 106

    Mohammad, H. P. & Kruger, R. G. Antitumor activity of LSD1 inhibitors in lung cancer. Mol. Cell. Oncol. 3, e1117700 (2016).

  107. 107

    Mohammad, H. P. et al. A DNA hypomethylation signature predicts antitumor activity of LSD1 inhibitors in SCLC. Cancer Cell 28, 57–69 (2015).

  108. 108

    Christensen, C. L. et al. Targeting transcriptional addictions in small cell lung cancer with a covalent CDK7 inhibitor. Cancer Cell 26, 909–922 (2014).

  109. 109

    Wu, N. et al. NFIB overexpression cooperates with Rb/p53 deletion to promote small cell lung cancer. Oncotarget 7, 57514–57524 (2016).

  110. 110

    Semenova, E. A. et al. Transcription factor NFIB is a driver of small cell lung cancer progression in mice and marks metastatic disease in patients. Cell Rep. 16, 631–643 (2016).

  111. 111

    Denny, S. K. et al. Nfib promotes metastasis through a widespread increase in chromatin accessibility. Cell 166, 328–342 (2016). This study shows that NFIB acts an oncogene, promoting metastasis in SCLC.

  112. 112

    Minna, J. D. & Johnson, J. E. Opening a chromatin gate to metastasis. Cell 166, 275–276 (2016).

  113. 113

    Polley, E. et al. Small cell lung cancer cell line screen of oncology drugs and investigational agents identifies patterns with gene and microRNA expression. J. Natl Cancer Inst. 108, djw122 (2016).

  114. 114

    Carter, L. et al. Molecular analysis of circulating tumor cells identifies distinct copy-number profiles in patients with chemosensitive and chemorefractory small-cell lung cancer. Nat. Med. 23, 114–119 (2017).

  115. 115

    Mavrommatis, E., Fish, E. N. & Platanias, L. C. The schlafen family of proteins and their regulation by interferons. J. Interferon Cytokine Res. 33, 206–210 (2013).

  116. 116

    Murai, J. et al. Resistance to PARP inhibitors by SLFN11 inactivation can be overcome by ATR inhibition. Oncotarget 7, 76534–76550 (2016).

  117. 117

    Berns, K. & Berns, A. Awakening of “Schlafen11” to tackle chemotherapy resistance in SCLC. Cancer Cell 31, 169–171 (2017).

  118. 118

    He, T. et al. Methylation of SLFN11 is a marker of poor prognosis and cisplatin resistance in colorectal cancer. Epigenomics 9, 849–862 (2017).

  119. 119

    Tripathi, S. C. et al. MCAM mediates chemoresistance in small cell lung cancer via the PI3K/AKT/SOX2 signaling pathway. Cancer Res. 77, 4414–4425 (2017).

  120. 120

    Sen, T. et al. CHK1 inhibition in small cell lung cancer produces single-agent activity in biomarker-defined disease subsets and combination activity with cisplatin or olaparib. Cancer Res. 77, 3870–3884 (2017).

  121. 121

    Cardnell, R. J. et al. Activation of the PI3K/mTOR pathway following PARP inhibition in small cell lung cancer. PLoS ONE 11, e0152584 (2016).

  122. 122

    Pietanza, M. C., Byers, L. A., Minna, J. D. & Rudin, C. M. Small cell lung cancer: will recent progress lead to improved outcomes? Clin. Cancer Res. 21, 2244–2255 (2015).

  123. 123

    Stewart, C. A. et al. Dynamic variations in epithelial-to-mesenchymal transition (EMT), ATM, and SLFN11 govern response to PARP inhibitors and cisplatin in small cell lung cancer. Oncotarget 8, 28575–28587 (2017).

  124. 124

    Fujita, K. et al. Cancer therapy due to apoptosis: galectin-9. Int. J. Mol. Sci. 18, 74 (2017).

  125. 125

    Takahashi, T. et al. p53: a frequent target for genetic abnormalities in lung cancer. Science 246, 491–494 (1989).

  126. 126

    Brambilla, E. & Gazdar, A. Pathogenesis of lung cancer signalling pathways: roadmap for therapies. Eur. Respir. J. 33, 1485–1497 (2009).

  127. 127

    Vogler, M. Targeting BCL2-proteins for the treatment of solid tumours. Adv. Med. 2014, 943648 (2014).

  128. 128

    Rosell, R. & Wannesson, L. A genetic snapshot of small cell lung cancer. Cancer Discov. 2, 769–771 (2012).

  129. 129

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

  130. 130

    Horn, L., Reck, M. & Spigel, D. R. The future of immunotherapy in the treatment of small cell lung cancer. Oncologist 21, 910–921 (2016).

  131. 131

    Reck, M., Heigener, D. & Reinmuth, N. Immunotherapy for small-cell lung cancer: emerging evidence. Future Oncol. 12, 931–943 (2016).

  132. 132

    Freeman-Keller, M., Goldman, J. & Gray, J. Vaccine immunotherapy in lung cancer: clinical experience and future directions. Pharmacol. Ther. 153, 1–9 (2015).

  133. 133

    Ehrlich, D., Wang, B., Lu, W., Dowling, P. & Yuan, R. Intratumoral anti-HuD immunotoxin therapy for small cell lung cancer and neuroblastoma. J. Hematol. Oncol. 7, 91 (2014).

  134. 134

    Weiskopf, K. et al. CD47-blocking immunotherapies stimulate macrophage-mediated destruction of small-cell lung cancer. J. Clin. Invest. 126, 2610–2620 (2016).

  135. 135

    Rolfo, C. et al. Liquid biopsies in lung cancer: the new ambrosia of researchers. Biochim. Biophys. Acta 1846, 539–546 (2014).

  136. 136

    Foy, V., Fernandez-Gutierrez, F., Faivre-Finn, C., Dive, C. & Blackhall, F. The clinical utility for circulating tumour cells in patients with small cell lung cancer. Transl Lung Cancer Res. 6, 409–417 (2017). This review describes an important new model system, namely, the establishment of xenografts from circulating SCLC tumour cells.

  137. 137

    Endo, H. et al. Spheroid culture of primary lung cancer cells with neuregulin 1/HER3 pathway activation. J. Thorac Oncol. 8, 131–139 (2013).

  138. 138

    Morrison, B. J., Morris, J. C. & Steel, J. C. Lung cancer-initiating cells: a novel target for cancer therapy. Target Oncol. 8, 159–172 (2013).

  139. 139

    Paraschiv, B., Diaconu, C. C., Toma, C. L. & Bogdan, M. A. Paraneoplastic syndromes: the way to an early diagnosis of lung cancer. Pneumologia 64, 14–19 (2015).

  140. 140

    Kanaji, N. et al. Paraneoplastic syndromes associated with lung cancer. World J. Clin. Oncol. 5, 197–223 (2014).

  141. 141

    Brown, W. A case of pluriglandular syndrome: “Diabetes of bearded women”. Lancet 212, 1022–1023 (1928).

  142. 142

    Cuttitta, F. et al. Bombesin-like peptides can function as autocrine growth factors in human small-cell lung cancer. Nature 316, 823–826 (1985).

  143. 143

    Callison, J. C. Jr, Walker, R. C. & Massion, P. P. Somatostatin receptors in lung cancer: from function to molecular imaging and therapeutics. J. Lung Cancer 10, 69–76 (2011).

  144. 144

    Titulaer, M. J., Lang, B. & Verschuuren, J. J. Lambert-Eaton myasthenic syndrome: from clinical characteristics to therapeutic strategies. Lancet Neurol. 10, 1098–1107 (2011).

  145. 145

    Swarts, D. R., Ramaekers, F. C. & Speel, E. J. Molecular and cellular biology of neuroendocrine lung tumors: evidence for separate biological entities. Biochim. Biophys. Acta 1826, 255–271 (2012).

  146. 146

    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).

  147. 147

    Zelen, M. Keynote address on biostatistics and data retrieval. Cancer Chemother. Rep. 3, 31–42 (1973).

  148. 148

    Pearse, A. G. Common cytochemical and ultrastructural characteristics of cells producing polypeptide hormones (the APUD series) and their relevance to thyroid and ultimobranchial C cells and calcitonin. Proc. R. Soc. Lond. B Biol. Sci. 170, 71–80 (1968).

  149. 149

    Haddadin, S. & Perry, M. C. History of small-cell lung cancer. Clin. Lung Cancer 12, 87–93 (2011).

  150. 150

    Oboshi, S. et al. A new floating cell line derived from human pulmonary carcinoma of oat cell type. Jpn. J. Cancer Res. 62, 505–514 (1971).

  151. 151

    Gewirtz, G. & Yalow, R. S. Ectopic ACTH production in carcinoma of the lung. J. Clin. Invest. 53, 1022–1032 (1974).

  152. 152

    Pettengill, O. S. et al. Isolation and growth characteristics of continuous cell lines from small-cell carcinoma of the lung. Cancer 45, 906–918 (1980).

  153. 153

    Harbour, J. W. et al. Abnormalities in structure and expression of the human retinoblastoma gene in SCLC. Science 241, 353–357 (1988).

  154. 154

    Meuwissen, R. & Berns, A. Mouse models for human lung cancer. Genes Dev. 19, 643–664 (2005).

  155. 155

    Shepherd, F. A. et al. The International Association for the Study of Lung Cancer lung cancer staging project: proposals regarding the clinical staging of small cell lung cancer in the forthcoming (seventh) edition of the tumor, node, metastasis classification for lung cancer. J. Thorac Oncol. 2, 1067–1077 (2007).

  156. 156

    Spigel, D. R. & Socinski, M. A. Rationale for chemotherapy, immunotherapy, and checkpoint blockade in SCLC: beyond traditional treatment approaches. J. Thorac Oncol. 8, 587–598 (2013).

  157. 157

    Rudin, C. M. et al. Rovalpituzumab tesirine, a DLL3-targeted antibody-drug conjugate, in recurrent small-cell lung cancer: a first-in-human, first-in-class, open-label, phase 1 study. Lancet Oncol. 18, 42–51 (2017).

  158. 158

    Sutherland, K. D. et al. Cell of origin of small cell lung cancer: inactivation of Trp53 and Rb1 in distinct cell types of adult mouse lung. Cancer Cell 19, 754–764 (2011).

  159. 159

    Guo, L., Zhang, T., Xiong, Y. & Yang, Y. Roles of NOTCH1 as a therapeutic target and a biomarker for lung cancer: controversies and perspectives. Dis. Markers 2015, 520590 (2015).

  160. 160

    Alketbi, A. & Attoub, S. Notch signaling in cancer: rationale and strategies for targeting. Curr. Cancer Drug Targets 15, 364–374 (2015).

  161. 161

    Falix, F. A., Aronson, D. C., Lamers, W. H. & Gaemers, I. C. Possible roles of DLK1 in the Notch pathway during development and disease. Biochim. Biophys. Acta 1822, 988–995 (2012).

  162. 162

    Nueda, M. L., Naranjo, A. I., Baladron, V. & Laborda, J. The proteins DLK1 and DLK2 modulate NOTCH1-dependent proliferation and oncogenic potential of human SK-MEL-2 melanoma cells. Biochim. Biophys. Acta 1843, 2674–2684 (2014).

  163. 163

    Dammann, R. et al. Epigenetic inactivation of a RAS association domain family protein from the lung tumour suppressor locus 3p21.3. Nat. Genet. 25, 315–319 (2000).

  164. 164

    Wang, Y. W. et al. ITPKA gene body methylation regulates gene expression and serves as an early diagnostic marker in lung and other cancers. J. Thorac Oncol. 11, 1469–1481 (2016).

  165. 165

    Niu, Y. et al. Long non-coding RNA TUG1 is involved in cell growth and chemoresistance of small cell lung cancer by regulating LIMK2b via EZH2. Mol. Cancer 16, 5 (2017).

  166. 166

    Fang, S. et al. Long noncoding RNA-HOTAIR affects chemoresistance by regulating HOXA1 methylation in small cell lung cancer cells. Lab. Invest. 96, 60–68 (2016).

  167. 167

    Pettengill, O. S., Carney, D. N., Sorenson, G. D. & Gazdar, A. F. in The Endocrine Lung in Health and Disease (eds Becker, K. L. & Gazdar, A. F.) 460–468 (1984).

  168. 168

    Phelps, R. M. et al. NCI-Navy Medical Oncology Branch cell line data base. J. Cell. Biochem. Suppl. 24, 32–91 (1996).

  169. 169

    Gazdar, A. F. & Minna, J. D. NCI series of cell lines: an historical perspective. J. Cell. Biochem. Suppl. 24, 1–11 (1996).

  170. 170

    Simms, E., Gazdar, A. F., Abrams, P. G. & Minna, J. D. Growth of human small cell (oat cell) carcinoma of the lung in serum-free growth factor-supplemented medium. Cancer Res. 40, 4356–4363 (1980).

  171. 171

    Carney, D. N., Bepler, G. & Gazdar, A. F. The serum-free establishment and in vitro growth properties of classic and variant small cell lung cancer cell lines. Recent Results Cancer Res. 99, 157–166 (1985).

  172. 172

    Ramirez, R. D. et al. Immortalization of human bronchial epithelial cells in the absence of viral oncoproteins. Cancer Res. 64, 9027–9034 (2004).

  173. 173

    Sato, M. et al. Human lung epithelial cells progressed to malignancy through specific oncogenic manipulations. Mol. Cancer Res. 11, 638–650 (2013).

  174. 174

    Berns, A. & Barbacid, M. Mouse models of cancer. Mol. Oncol. 7, 143–145 (2013).

  175. 175

    Gazdar, A. F., Hirsch, F. R. & Minna, J. D. From mice to men and back: an assessment of preclinical model systems for the study of lung cancers. J. Thorac Oncol. 11, 287–299 (2016).

  176. 176

    Singh, M., Murriel, C. L. & Johnson, L. Genetically engineered mouse models: closing the gap between preclinical data and trial outcomes. Cancer Res. 72, 2695–2700 (2012).

  177. 177

    Kellar, A., Egan, C. & Morris, D. Preclinical murine models for lung cancer: clinical trial applications. BioMed Res. Int. 2015, 621324 (2015).

  178. 178

    Vikis, H. G., Rymaszewski, A. L. & Tichelaar, J. W. Mouse models of chemically-induced lung carcinogenesis. Front. Biosci. 5, 939–946 (2013).

  179. 179

    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).

  180. 180

    Lázaro, S. et al. Ablating all three retinoblastoma family members in mouse lung leads to neuroendocrine tumor formation. Oncotarget 8, 4373–4386 (2016).

  181. 181

    Isobe, T. et al. Evaluation of novel orthotopic nude mouse models for human small-cell lung cancer. J. Thorac Oncol. 8, 140–146 (2013).

  182. 182

    Némati, F. et al. Clinical relevance of human cancer xenografts as a tool for preclinical assessment: example of in-vivo evaluation of topotecan-based chemotherapy in a panel of human small-cell lung cancer xenografts. Anticancer Drugs 21, 25–32 (2010).

  183. 183

    Sakamoto, S. et al. New metastatic model of human small-cell lung cancer by orthotopic transplantation in mice. Cancer Sci. 106, 367–374 (2015).

  184. 184

    Chambers, W. F., Pettengill, O. S. & Sorenson, G. D. Intracranial growth of pulmonary small cell carcinoma cells in nude athymic mice. Exp. Cell Biol. 49, 90–97 (1981).

  185. 185

    Gazdar, A. F., Carney, D. N., Sims, H. L. & Simmons, A. Heterotransplantation of small-cell carcinoma of the lung into nude mice: comparison of intracranial and subcutaneous routes. Int. J. Cancer 28, 777–783 (1981).

  186. 186

    Malaney, P., Nicosia, S. V. & Dave, V. One mouse, one patient paradigm: new avatars of personalized cancer therapy. Cancer Lett. 344, 1–12 (2014).

Download references

Acknowledgements

This work was supported by grants from the National Cancer Institute, Bethesda, Maryland, USA: 'Specialized Program in Research Excellence in Lung Cancer', P50 CA70907 and the 'Small Cell Lung Cancer Consortium Coordinating Center' U24CA213274 (A.F.G. and J.D.M.) and the 'Colorado Lung Cancer SPORE' P50-CA058187 (P.A.B.).

Author information

A.F.G, P.A.B. and J.D.M. researched data for the article, made substantial contributions to discussions of the content, wrote the article and reviewed and edited the manuscript before submission.

Correspondence to Adi F. Gazdar.

Ethics declarations

Competing interests

J.D.M. and A.F.G. receive licensing fees for the lung cancer cell lines they have established. P.A.B. serves as a consultant and advisory board member for AstraZeneca.

Related links

PowerPoint slides

Supplementary information

Supplementary information

Supplementary information S1 (table) (DOCX 30 kb)

Glossary

Master regulator

Genes at the top of the gene regulation hierarchy, especially in regulatory pathways controlling cell fate or differentiation.

Lineage-specific oncogene

A gene that directs lineage-restricted programmes to drive crucial developmental processes such as chromatin remodelling and specific transcriptional events, controls proliferation and survival mechanisms and promotes tumour formation in relevant precursor cells.

Classic subtype of SCLC

The classic subtype refers to the usual recognized form of SCLC, with typical morphology, expression of neuroendocrine (NE) properties and a non-adherent growth pattern in vitro.

Variant subtype of SCLC

The variant subtype, often recognized after therapy, is characterized by larger cells with prominent nucleoli, partial or complete loss of neuroendocrine (NE) cell properties, partial adherent growth in vitro, frequent MYC amplification and epithelial–mesenchymal transition.

Transdifferentiation

The switch, in malignant or non-malignant stem cells, from one form of differentiation to another.

APOBEC signature

Apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (APOBEC) cytidine deaminases convert cytosine to uracil during RNA editing. Smoking-related cancers, including lung cancers, express genes related to increased mutagenesis and exhibit a characteristic APOBEC mutation signature within tumour DNA.

Cancer field effects

Preneoplastic, preinvasive and invasive lesions that may develop over a lengthy period of time as a result of oncogenic exposure (such as from smoking) that damages the entire field at risk (such as the respiratory epithelium).

Enhancer of zeste homologue 2

(EZH2). The catalytic subunit of the Polycomb repressive complex 2, which is overexpressed in many tumours and plays a role in stem cell maintenance. It also plays a crucial role in methylation via chromatin modification and activation of DNA methyltransferases.

Bromodomain and extra-terminal domain (BET) family

A family of proteins that contain bromodomains that recognize acetylated lysine residues on the N-terminal tails of histones and regulate gene expression via chromatin remodelling.

Super-enhancers

Genomic regions comprising multiple enhancers that are commonly identified by enriched domains of chromatin marked by acetylated histone H3 lysine 27 and are associated with lineage specificity and key oncogenes in cancers.

Schlafen family of proteins

Schlafen (SLFN) proteins that are involved in important functions, including cell proliferation, immune responses and the regulation of viral replication.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Gazdar, A., Bunn, P. & Minna, J. Small-cell lung cancer: what we know, what we need to know and the path forward. Nat Rev Cancer 17, 725–737 (2017) doi:10.1038/nrc.2017.87

Download citation

Further reading