Origins, genetic landscape, and emerging therapies of small cell lung cancer

Ekaterina A Semenova, Remco Nagel, Anton Berns, Ekaterina A Semenova, Remco Nagel, Anton Berns

Abstract

Lung cancer is the leading cause of cancer deaths, with small cell lung cancer (SCLC) representing the most aggressive subtype. Standard treatments have not changed in decades, and the 5-year survival rate has remained <7%. Genomic analyses have identified key driver mutations of SCLC that were subsequently validated in animal models of SCLC. To provide better treatment options, a deeper understanding of the cellular and molecular mechanisms underlying SCLC initiation, progression, metastasis, and acquisition of resistance is required. In this review, we describe the genetic landscape of SCLC, features of the cell of origin, and targeted therapeutic approaches.

Keywords: GEMM; SCLC; cell of origin; driver; neuroendocrine; targeted therapy.

© 2015 Semenova et al.; Published by Cold Spring Harbor Laboratory Press.

Figures

Figure 1.
Figure 1.
Structure and cell types of the respiratory system. (A) Expression of Dll1-LacZ (white arrows) in presumptive NE cells within proximal airways at E14.5. (Republished with permission of Annual Reviews from Rock and Hogan 2011; permission conveyed through the Copyright Clearance Center, Inc.) (B) Schematic of human and mouse lungs with epithelial histology of regions along the proximal–distal axis. (Republished with permission of Elsevier from Hogan et al. 2014; permission conveyed through Copyright Clearance Center, Inc.) (Left panel) The human trachea, bronchi, and bronchioles >1 mm in diameter are lined by a pseudostratified epithelium with basal, multiciliated, and secretory club cells. Club cells predominate in the small airways. The alveoli are lined by squamous AEC1s and cuboidal AEC2s. (Right panel) In mice, only the trachea and main stem bronchi are lined by a pseudostratified mucociliary epithelium with basal cells. The smaller bronchi and bronchioles are lined by a simple epithelium with multiciliated and club cells. The inset illustrates a mouse lung to the same scale as the human lung in the left panel. (C) Schematic representation of individual cell types within the mouse respiratory epithelial system. (Republished with permission of Annual Reviews from Rock and Hogan 2011; permission conveyed through the Copyright Clearance Center, Inc.) (D) Section of the adult mouse lung, with rare NE cells marked by the expression of synaptophysin (brown). Bars: 100 μm; inset, 20 μm.

References

    1. Adachi J, Ookawa K, Shiseki M, Okazaki T, Tsuchida S, Morishita K, Yokota J. 1996. Induction of apoptosis but not G1 arrest by expression of the wild-type p53 gene in small cell lung carcinoma. Cell Growth Differ 7: 879–886.
    1. Alexandrov LB, Nik-Zainal S, Wedge DC, Aparicio SAJR, Behjati S, Biankin AV, Bignell GR, Bolli N, Borg A, Børresen-Dale A-L, et al. 2013. Signatures of mutational processes in human cancer. Nature 500: 415–421.
    1. Ali FR, Cheng K, Kirwan P, Metcalfe S, Livesey FJ, Barker RA, Philpott A. 2014. The phosphorylation status of Ascl1 is a key determinant of neuronal differentiation and maturation in vivo and in vitro. Development 141: 2216–2224.
    1. Azzopardi JG. 1959. Oat-cell carcinoma of the bronchus. J Pathol Bacteriol 78: 513–519.
    1. Baggstrom MQ, Qi Y, Koczywas M, Argiris A, Johnson EA, Millward MJ, Murphy SC, Erlichman C, Rudin CM, Govindan R. 2011. A phase II study of AT-101 (Gossypol) in chemotherapy-sensitive recurrent extensive-stage small cell lung cancer. J Thorac Oncol 6: 1757–1760.
    1. Barnard WG. 1926. The nature of the ‘oat-celled sarcoma’ of the mediastinum. J Pathol Bacteriol 29: 241–244.
    1. Bensch KG, Gordon GB, Miller LR. 1965. Electron microscopic and biochemical studies on the bronchial carcinoid tumor. Cancer 18: 592–602.
    1. Bensch KG, Corrin B, Pariente R, Spencer H. 1968. Oat-cell carcinoma of the lung. Its origin and relationship to bronchial carcinoid. Cancer 22: 1163–1172.
    1. Bhattacharjee A, Richards WG, Staunton J, Li C, Monti S, Vasa P, Ladd C, Beheshti J, Bueno R, Gillette M, et al. 2001. Classification of human lung carcinomas by mRNA expression profiling reveals distinct adenocarcinoma subclasses. Proc Natl Acad Sci 98: 13790–13795.
    1. Borges M, Linnoila RI, van de Velde HJ, Chen H, Nelkin BD, Mabry M, Baylin SB, Ball DW. 1997. An achaete-scute homologue essential for neuroendocrine differentiation in the lung. Nature 386: 852–855.
    1. Bracci L, Schiavoni G, Sistigu A, Belardelli F. 2013. Immune-based mechanisms of cytotoxic chemotherapy: implications for the design of novel and rationale-based combined treatments against cancer. Cell Death Differ 21: 15–25.
    1. Brennan J, O'Connor T, Makuch RW, Simmons AM, Russell E, Linnoila RI, Phelps RM, Gazdar AF, Ihde DC, Johnson BE. 1991. 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.
    1. Brown SD, Warren RL, Gibb EA, Martin SD, Spinelli JJ, Nelson BH, Holt RA. 2014. Neo-antigens predicted by tumor genome meta-analysis correlate with increased patient survival. Genome Res 24: 743–750.
    1. Byers LA, Rudin CM. 2014. Small cell lung cancer: where do we go from here? Cancer 121: 664–672.
    1. Byers LA, Wang J, Nilsson MB, Fujimoto J, Saintigny P, Yordy J, Giri U, Peyton M, Fan YH, Diao L, et al. 2012. Proteomic profiling identifies dysregulated pathways in small cell lung cancer and novel therapeutic targets including PARP1. Cancer Discov 2: 798–811.
    1. Calbo J, van Montfort E, Proost N, van Drunen E, Beverloo HB, Meuwissen R, Berns A. 2011. A functional role for tumor cell heterogeneity in a mouse model of small cell lung cancer. Cancer Cell 19: 244–256.
    1. Cardnell RJ, Feng Y, Diao L, Fan Y-H, Masrorpour F, Wang J, Shen Y, Mills GB, Minna JD, Heymach JV, et al. 2013. Proteomic markers of DNA repair and PI3K pathway activation predict response to the PARP inhibitor BMN 673 in small cell lung cancer. Clin Cancer Res 19: 6322–6328.
    1. Cardoso WV. 2006. Regulation of early lung morphogenesis: questions, facts and controversies. Development 133: 1611–1624.
    1. Carvajal LA, Manfredi JJ. 2013. Another fork in the road—life or death decisions by the tumour suppressor p53. EMBO Rep 14: 414–421.
    1. Chanda S, Ang CE, Davila J, Pak C, Mall M, Lee QY, Ahlenius H, Jung SW, Südhof TC, Wernig M. 2014. Generation of induced neuronal cells by the single reprogramming factor ASCL1. Stem Cell Rep 3: 282–296.
    1. Chappell J, Dalton S. 2013. Roles for MYC in the establishment and maintenance of pluripotency. Cold Spring Harb Perspect Med 3: a014381.
    1. Cheng AW, Wang H, Yang H, Shi L, Katz Y, Theunissen TW, Rangarajan S, Shivalila CS, Dadon DB, Jaenisch R. 2013. Multiplexed activation of endogenous genes by CRISPR-on, an RNA-guided transcriptional activator system. Cell Res 23: 1163–1171.
    1. Christensen CL, Kwiatkowski N, Abraham BJ, Carretero J, Al-Shahrour F, Zhang T, Chipumuro E, Herter-Sprie GS, Akbay EA, Altabef A, et al. 2014. Targeting transcriptional addictions in small cell lung cancer with a covalent CDK7 inhibitor. Cancer Cell 26: 909–922.
    1. Chute JP, Chen T, Feigal E, Simon R, Johnson BE. 1999. Twenty years of phase III trials for patients with extensive-stage small-cell lung cancer: perceptible progress. J Clin Oncol 17: 1794–1801.
    1. Coe BP, Thu KL, Aviel-Ronen S, Vucic EA, Gazdar AF, Lam S, Tsao M-S, Lam WL. 2013. Genomic deregulation of the E2F/Rb pathway leads to activation of the oncogene EZH2 in small cell lung cancer. PLoS One 8: e71670.
    1. Cui M, Augert A, Rongione M, Conkrite K, Parazzoli S, Nikitin AY, Ingolia N, MacPherson D. 2014. PTEN is a potent suppressor of small cell lung cancer. Mol Cancer Res 12: 654–659.
    1. Daniel VC, Marchionni L, Hierman JS, Rhodes JT, Devereux WL, Rudin CM, Yung R, Parmigiani G, Dorsch M, Peacock CD, et al. 2009. A primary xenograft model of small-cell lung cancer reveals irreversible changes in gene expression imposed by culture in vitro. Cancer Res 69: 3364–3373.
    1. Delmore JE, Issa GC, Lemieux ME, Rahl PB, Shi J, Jacobs HM, Kastritis E, Gilpatrick T, Paranal RM, Qi J, et al. 2011. BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell 146: 904–917.
    1. Doyle A, Martin WJ, Funa K, Gazdar A, Carney D, Martin SE, Linnoila I, Cuttitta F, Mulshine J, Bunn P. 1985. Markedly decreased expression of class I histocompatibility antigens, protein, and mRNA in human small-cell lung cancer. J Exp Med 161: 1135–1151.
    1. Duffy MJ, Synnott NC, McGowan PM, Crown J, O'Connor D, Gallagher WM. 2014. p53 as a target for the treatment of cancer. Cancer Treat Rev 40: 1153–1160.
    1. Faber AC, Farago AF, Costa C, Dastur A, Gomez-Caraballo M, Robbins R, Wagner BL, Rideout WM, Jakubik CT, Ham J, et al. 2015. Assessment of ABT-263 activity across a cancer cell line collection leads to a potent combination therapy for small-cell lung cancer. Proc Natl Acad Sci 112: E1288–E1296.
    1. Fanidi A, Harrington EA, Evan GI. 1992. Cooperative interaction between c-myc and bcl-2 proto-oncogenes. Nature 359: 554–556.
    1. Ferlay J, Shin H-R, Bray F, Forman D, Mathers C, Parkin DM. 2010. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 127: 2893–2917.
    1. Forgacs E, Biesterveld EJ, Sekido Y, Fong K, Muneer S, Wistuba II, Milchgrub S, Brezinschek R, Virmani A, Gazdar AF, et al. 1998. Mutation analysis of the PTEN/MMAC1 gene in lung cancer. Oncogene 17: 1557–1565.
    1. Friend SH, Dryja TP, Weinberg RA. 1988. Oncogenes and tumor-suppressing genes. N Engl J Med 318: 618–622.
    1. Gazdar AF, Minna JD. 1996. NCI series of cell lines: an historical perspective. J Cell Biochem Suppl 24: 1–11.
    1. Gazdar AF, Gao B, Minna JD. 2010. Lung cancer cell lines: useless artifacts or invaluable tools for medical science? Lung Cancer 68: 309–318.
    1. Gazdar AF, Savage TK, Johnson JE, Berns A, Sage J, Linnoila RI, MacPherson D, McFadden DG, Farago A, Jacks T, et al. 2015. The comparative pathology of genetically engineered mouse models for neuroendocrine carcinomas of the lung. J Thorac Oncol 10: 553–564.
    1. George J, Lim JS, Jang SJ, Cun Y, Ozretic L, Kong G, Leenders F, Lu X, Fernández-Cuesta L, Bosco G, et al. 2015. Comprehensive genomic profiles of small cell lung cancer. Nature 10.1038/nature14664.
    1. Govindan R. 2006. 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.
    1. Grandori C, Eisenman RN. 1997. Myc target genes. Trends Biochem Sci 22: 177–181.
    1. Gu J, Linnoila RI, Seibel NL, Gazdar AF, Minna JD, Brooks BJ, Hollis GF, Kirsch IR. 1988. A study of myc-related gene expression in small cell lung cancer by in situ hybridization. Am J Pathol 132: 13–17.
    1. Gustafson WC, Meyerowitz JG, Nekritz EA, Chen J, Benes C, Charron E, Simonds EF, Seeger R, Matthay KK, Hertz NT, et al. 2014. Drugging MYCN through an allosteric transition in Aurora kinase A. Cancer Cell 26: 414–427.
    1. Harbour JW, Lai SL, Whang-Peng J, Gazdar AF, Minna JD, Kaye FJ. 1988. Abnormalities in structure and expression of the human retinoblastoma gene in SCLC. Science 241: 353–357.
    1. Hattori S, Matsuda M, Tateishi R, Nishihara H, Horai T. 1972. Oat-cell carcinoma of the lung. Clinical and morphological studies in relation to its histogenesis. Cancer 30: 1014–1024.
    1. Helin K, Holm K, Niebuhr A, Eiberg H, Tommerup N, Hougaard S, Poulsen HS, Spang-Thomsen M, Norgaard P. 1997. Loss of the retinoblastoma protein-related p130 protein in small cell lung carcinoma. Proc Natl Acad Sci 94: 6933–6938.
    1. Hodgkinson CL, Morrow CJ, Li Y, Metcalf RL, Rothwell DG, Trapani F, Polanski R, Burt DJ, Simpson KL, Morris K, et al. 2014. Tumorigenicity and genetic profiling of circulating tumor cells in small-cell lung cancer. Nat Med 20: 897–903.
    1. Hogan BLM, Barkauskas CE, Chapman HA, Epstein JA, Jain R, Hsia CCW, Niklason L, Calle E, Le A, Randell SH, et al. 2014. Repair and regeneration of the respiratory system: complexity, plasticity, and mechanisms of lung stem cell function. Stem Cell 15: 123–138.
    1. Hong KU, Reynolds SD, Giangreco A, Hurley CM, Stripp BR. 2001. Clara cell secretory protein-expressing cells of the airway neuroepithelial body microenvironment include a label-retaining subset and are critical for epithelial renewal after progenitor cell depletion. Am J Respir Cell Mol Biol 24: 671–681.
    1. Hsu PD, Lander ES, Zhang F. 2014. Development and applications of CRISPR–Cas9 for genome engineering. Cell 157: 1262–1278.
    1. Hubaux R, Thu KL, Coe BP, MacAulay C, Lam S, Lam WL. 2013. EZH2 promotes E2F-driven SCLC tumorigenesis through modulation of apoptosis and cell-cycle regulation. J Thorac Oncol 8: 1102–1106.
    1. Huijbers IJ, Bin Ali R, Pritchard C, Cozijnsen M, Kwon M-C, Proost N, Song J-Y, de Vries H, Badhai J, Sutherland K, et al. 2014. Rapid target gene validation in complex cancer mouse models using re-derived embryonic stem cells. EMBO Molecular Medicine 6: 212–225.
    1. Ito T, Udaka N, Yazawa T, Okudela K, Hayashi H, Sudo T, Guillemot F, Kageyama R, Kitamura H. 2000. Basic helix–loop–helix transcription factors regulate the neuroendocrine differentiation of fetal mouse pulmonary epithelium. Development 127: 3913–3921.
    1. Jackman DM, Johnson BE. 2005. Small-cell lung cancer. Lancet 366: 1385–1396.
    1. Jahchan NS, Dudley JT, Mazur PK, Flores N, Yang D, Palmerton A, Zmoos A-F, Vaka D, Tran KQT, Zhou M, et al. 2013. A drug repositioning approach identifies tricyclic antidepressants as inhibitors of small cell lung cancer and other neuroendocrine tumors. Cancer Discov 3: 1364–1377.
    1. Jalal S, Bedano P, Einhorn L, Bhatia S, Ansari R, Bechar N, Koneru K, Govindan R, Wu J, Yu M, et al. 2010. Paclitaxel plus bevacizumab in patients with chemosensitive relapsed small cell lung cancer: a safety, feasibility, and efficacy study from the Hoosier Oncology Group. J Thorac Oncol 5: 2008–2011.
    1. Jiang SX, Sato Y, Kuwao S, Kameya T. 1995. Expression of bcl-2 oncogene protein is prevalent in small cell lung carcinomas. J Pathol 177: 135–138.
    1. Johnson DH. 1999. Management of small cell lung cancer: current state of the art. Chest 116: 525S–530S.
    1. Johnson BE, Russell E, Simmons AM, Phelps R, Steinberg SM, Ihde DC, Gazdar AF. 1996. MYC family DNA amplification in 126 tumor cell lines from patients with small cell lung cancer. J Cell Biochem Suppl 24: 210–217.
    1. Kalemkerian GP, Akerley W, Bogner P, Borghaei H, Chow LQ, Downey RJ, Gandhi L, Ganti AKP, Govindan R, Grecula JC, et al. 2013. Small cell lung cancer. J Natl Compr Canc Netw 11: 78–98.
    1. Kamangar F, Dores GM, Anderson WF. 2006. Patterns of cancer incidence, mortality, and prevalence across five continents: defining priorities to reduce cancer disparities in different geographic regions of the world. J Clin Oncol 24: 2137–2150.
    1. Kareta MS, Gorges LL, Hafeez S, Benayoun BA, Marro S, Zmoos A-F, Cecchini MJ, Spacek D, Batista LFZ, O'Brien M, et al. 2015. Inhibition of pluripotency networks by the Rb tumor suppressor restricts reprogramming and tumorigenesis. Stem Cell 16: 39–50.
    1. Kato Y, Ferguson TB, Bennett DE, Burford TH. 1969. Oat cell carcinoma of the lung. A review of 138 cases. Cancer 23: 517–524.
    1. Kiefer PE, Bepler G, Kubasch M, Havemann K. 1987. Amplification and expression of protooncogenes in human small cell lung cancer cell lines. Cancer Res 47: 6236–6242.
    1. Kim YH, Girard L, Giacomini CP, Wang P, Hernandez-Boussard T, Tibshirani R, Minna JD, Pollack JR. 2006. Combined microarray analysis of small cell lung cancer reveals altered apoptotic balance and distinct expression signatures of MYC family gene amplification. Oncogene 25: 130–138.
    1. Kleinerman RA, Tarone RE, Abramson DH, Seddon JM, Li FP, Tucker MA. 2000. Hereditary retinoblastoma and risk of lung cancer. J Natl Cancer Inst 92: 2037–2039.
    1. Kotton DN, Morrisey EE. 2014. Lung regeneration: mechanisms, applications and emerging stem cell populations. Nat Med 20: 822–832.
    1. Krystal G, Birrer M, Way J, Nau M, Sausville E, Thompson C, Minna J, Battey J. 1988. Multiple mechanisms for transcriptional regulation of the myc gene family in small-cell lung cancer. Mol Cell Biol 8: 3373–3381.
    1. Kuiper JL, Heideman DAM, Thunnissen E, Paul MA, van Wijk AW, Postmus PE, Smit EF. 2014. Incidence of T790M mutation in (sequential) rebiopsies in EGFR-mutated NSCLC-patients. Lung Cancer 85: 19–24.
    1. Kwon M-c, Berns A. 2013. Mouse models for lung cancer. Mol Oncol 7: 165–177.
    1. Langer CJ, Albert I, Ross HJ, Kovacs P, Blakely LJ, Pajkos G, Somfay A, Zatloukal P, Kazarnowicz A, Moezi MM, et al. 2014. Randomized phase II study of carboplatin and etoposide with or without obatoclax mesylate in extensive-stage small cell lung cancer. Lung Cancer 85: 420–428.
    1. Leong TL, Marini KD, Rossello FJ, Jayasekara SN, Russell PA, Prodanovic Z, Kumar B, Ganju V, Alamgeer M, Irving LB, et al. 2014. Genomic characterisation of small cell lung cancer patient-derived xenografts generated from endobronchial ultrasound-guided transbronchial needle aspiration specimens. PLoS One 9: e106862.
    1. Linnoila RI. 2006. Functional facets of the pulmonary neuroendocrine system. Lab Invest 86: 425–444.
    1. Linnoila RI, Sahu A, Miki M, Ball DW, DeMayo FJ. 2000. Morphometric analysis of CC10-hASH1 transgenic mouse lung: a model for bronchiolization of alveoli and neuroendocrine carcinoma. Exp Lung Res 26: 595–615.
    1. Lu H-Y, Wang X-J, Mao W-M. 2013. Targeted therapies in small cell lung cancer. Oncol Lett 5: 3–11.
    1. Lucchi M, Mussi A, Fontanini G, Faviana P, Ribechini A, Angeletti CA. 2002. Small cell lung carcinoma (SCLC): the angiogenic phenomenon. Eur J Cardiothorac Surg 21: 1105–1110.
    1. McFadden DG, Papagiannakopoulos T, Taylor-Weiner A, Stewart C, Carter SL, Cibulskis K, Bhutkar A, McKenna A, Dooley A, Vernon A, et al. 2014. Genetic and clonal dissection of murine small cell lung carcinoma progression by genome sequencing. Cell 156: 1298–1311.
    1. Melichar B, Adenis A, Lockhart AC, Bennouna J, Dees EC, Kayaleh O, Obermannova R, DeMichele A, Zatloukal P, Zhang B, et al. 2015. Safety and activity of alisertib, an investigational aurora kinase A inhibitor, in patients with breast cancer, small-cell lung cancer, non-small-cell lung cancer, head and neck squamous-cell carcinoma, and gastro-oesophageal adenocarcinoma: a five-arm phase 2 study. Lancet Oncol 16: 395–405.
    1. Metzger RJ, Klein OD, Martin GR, Krasnow MA. 2008. The branching programme of mouse lung development. Nature 453: 745–750.
    1. Meuwissen R, Linn SC, Linnoila RI, Zevenhoven J, Mooi WJ, Berns A. 2003. Induction of small cell lung cancer by somatic inactivation of both Trp53 and Rb1 in a conditional mouse model. Cancer Cell 4: 181–189.
    1. Micke P, Faldum A, Metz T, Beeh K-M, Bittinger F, Hengstler J-G, Buhl R. 2002. Staging small cell lung cancer: Veterans Administration Lung Study Group versus International Association for the Study of Lung Cancer—what limits limited disease? Lung Cancer 37: 271–276.
    1. Miyashita T, Krajewski S, Krajewska M, Wang HG, Lin HK, Liebermann DA, Hoffman B, Reed JC. 1994. Tumor suppressor p53 is a regulator of bcl-2 and bax gene expression in vitro and in vivo. Oncogene 9: 1799–1805.
    1. Modi S, Kubo A, Oie H, Coxon AB, Rehmatulla A, Kaye FJ. 2000. Protein expression of the RB-related gene family and SV40 large T antigen in mesothelioma and lung cancer. Oncogene 19: 4632–4639.
    1. Morimoto M, Nishinakamura R, Saga Y, Kopan R. 2012. Different assemblies of Notch receptors coordinate the distribution of the major bronchial Clara, ciliated and neuroendocrine cells. Development 139: 4365–4373.
    1. Niederst MJ, Sequist LV, Poirier JT, Mermel CH, Lockerman EL, Garcia AR, Katayama R, Costa C, Ross KN, Moran T, et al. 2015. RB loss in resistant EGFR mutant lung adenocarcinomas that transform to small-cell lung cancer. Nat Commun 6: 6377.
    1. Norkowski E, Ghigna M-R, Lacroix L, Le Chevalier T, Fadel É, Dartevelle P, Dorfmuller P, Thomas de Montpréville V. 2013. Small-cell carcinoma in the setting of pulmonary adenocarcinoma: new insights in the era of molecular pathology. J Thorac Oncol 8: 1265–1271.
    1. Otterson G, Lin A, Kay F. 1992. Genetic etiology of lung cancer. Oncology 6: 97–104.
    1. Park K-S, Liang M-C, Raiser DM, Zamponi R, Roach RR, Curtis SJ, Walton Z, Schaffer BE, Roake CM, Zmoos A-F, et al. 2011a. Characterization of the cell of origin for small cell lung cancer. Cell Cycle 10: 2806–2815.
    1. Park K-S, Martelotto LG, Peifer M, Sos ML, Karnezis AN, Mahjoub MR, Bernard K, Conklin JF, Szczepny A, Yuan J, et al. 2011b. A crucial requirement for Hedgehog signaling in small cell lung cancer. Nat Med 17: 150–1508.
    1. Peifer M, Fernández-Cuesta L, Sos ML, George J, Seidel D, Kasper LH, Plenker D, Leenders F, Sun R, Zander T, et al. 2012. Integrative genome analyses identify key somatic driver mutations of small-cell lung cancer. Nat Genet 44: 1104–1110.
    1. Pereira JD, Sansom SN, Smith J, Dobenecker MW, Tarakhovsky A, Livesey FJ. 2010. Ezh2, the histone methyltransferase of PRC2, regulates the balance between self-renewal and differentiation in the cerebral cortex. Proc Natl Acad Sci 107: 15957–15962.
    1. Pezzella F, Turley H, Kuzu I, Tungekar MF, Dunnill MS, Pierce CB, Harris A, Gatter KC, Mason DY. 1993. bcl-2 protein in non-small-cell lung carcinoma. N Engl J Med 329: 690–694.
    1. Poirier JT, Gardner EE, Connis N, Moreira AL, de Stanchina E, Hann CL, Rudin CM. 2015. DNA methylation in small cell lung cancer defines distinct disease subtypes and correlates with high expression of EZH2. Oncogene 10.1038/onc.2015.38.
    1. Popat S, Wotherspoon A, Nutting CM, Gonzalez D, Nicholson AG, O'Brien M. 2013. Transformation to ‘high grade’ neuroendocrine carcinoma as an acquired drug resistance mechanism in EGFR-mutant lung adenocarcinoma. Lung Cancer 80: 1–4.
    1. Post LC, Ternet M, Hogan BL. 2000. Notch/Delta expression in the developing mouse lung. Mech Dev 98: 95–98.
    1. Rawlins EL, Clark CP, Xue Y, Hogan BLM. 2009. The Id2+ distal tip lung epithelium contains individual multipotent embryonic progenitor cells. Development 136: 3741–3745.
    1. Razzini G, Berrie CP, Vignati S, Broggini M, Mascetta G, Brancaccio A, Falasca M. 2000. Novel functional PI 3-kinase antagonists inhibit cell growth and tumorigenicity in human cancer cell lines. FASEB J 14: 1179–1187.
    1. Reits EA. 2006. Radiation modulates the peptide repertoire, enhances MHC class I expression, and induces successful antitumor immunotherapy. J Exp Med 203: 1259–1271.
    1. Renshaw AA, Haja J, Lozano RL, Wilbur DC. 2005. Distinguishing carcinoid tumor from small cell carcinoma of the lung: correlating cytologic features and performance in the College of American Pathologists Non-Gynecologic Cytology Program. Arch Pathol Lab Med 129: 614–618.
    1. Reynolds SD, Giangreco A, Power JH, Stripp BR. 2000. Neuroepithelial bodies of pulmonary airways serve as a reservoir of progenitor cells capable of epithelial regeneration. Am J Pathol 156: 269–278.
    1. Ried T, Petersen I, Holtgreve-Grez H, Speicher MR, Schröck E, du Manoir S, Cremer T. 1994. Mapping of multiple DNA gains and losses in primary small cell lung carcinomas by comparative genomic hybridization. Cancer Res 54: 1801–1806.
    1. Rock JR, Hogan BLM. 2011. Epithelial progenitor cells in lung development, maintenance, repair, and disease. Annu Rev Cell Dev Biol 27: 493–512.
    1. Rock JR, Randell SH, Hogan BLM. 2010. Airway basal stem cells: a perspective on their roles in epithelial homeostasis and remodeling. Dis Model Mech 3: 545–556.
    1. Ross JS, Wang K, Elkadi OR, Tarasen A, Foulke L, Sheehan CE, Otto GA, Palmer G, Yelensky R, Lipson D, et al. 2014. Next-generation sequencing reveals frequent consistent genomic alterations in small cell undifferentiated lung cancer. J Clin Pathol 67: 772–776.
    1. Rudin CM, Salgia R, Wang X, Hodgson LD, Masters GA, Green M, Vokes EE. 2008. Randomized phase II Study of carboplatin and etoposide with or without the bcl-2 antisense oligonucleotide oblimersen for extensive-stage small-cell lung cancer: CALGB 30103. J Clin Oncol 26: 870–876.
    1. Rudin CM, Durinck S, Stawiski EW, Poirier JT, Modrusan Z, Shames DS, Bergbower EA, Guan Y, Shin J, Guillory J, et al. 2012. Comprehensive genomic analysis identifies SOX2 as a frequently amplified gene in small-cell lung cancer. Nat Genet 44: 1111–1116.
    1. Rygaard K, Nakamura T, Spang-Thomsen M. 1993. Expression of the proto-oncogenes c-met and c-kit and their ligands, hepatocyte growth factor/scatter factor and stem cell factor, in SCLC cell lines and xenografts. Br J Cancer 67: 37–46.
    1. Salgia R, Skarin AT. 1998. Molecular abnormalities in lung cancer. J Clin Oncol 16: 1207–1217.
    1. Salven P, Ruotsalainen T, Mattson K, Joensuu H. 1998. High pre-treatment serum level of vascular endothelial growth factor (VEGF) is associated with poor outcome in small-cell lung cancer. Int J Cancer 79: 144–146.
    1. Sánchez-Rivera FJ, Papagiannakopoulos T, Romero R, Tammela T, Bauer MR, Bhutkar A, Joshi NS, Subbaraj L, Bronson RT, Xue W, et al. 2014. Rapid modelling of cooperating genetic events in cancer through somatic genome editing. Nature 516: 428–431.
    1. Schaffer BE, Park KS, Yiu G, Conklin JF, Lin C, Burkhart DL, Karnezis AN, Sweet-Cordero EA, Sage J. 2010. Loss of p130 accelerates tumor development in a mouse model for human small-cell lung carcinoma. Cancer Res 70: 3877–3883.
    1. Sellers WR, Novitch BG, Miyake S, Heith A, Otterson GA, Kaye FJ, Lassar AB, Kaelin WG. 1998. Stable binding to E2F is not required for the retinoblastoma protein to activate transcription, promote differentiation, and suppress tumor cell growth. Genes Dev 12: 95–106.
    1. Sequist LV, Waltman BA, Dias-Santagata D, Digumarthy S, Turke AB, Fidias P, Bergethon K, Shaw AT, Gettinger S, Cosper AK, et al. 2011. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med 3: 75ra26.
    1. Sgambato A, Casaluce F, Maione P, Rossi A, Sacco PC, Panzone F, Ciardiello F, Gridelli C. 2013. Medical treatment of small cell lung cancer: state of the art and new development. Expert Opin Pharmacother 14: 2019–2031.
    1. Shepherd FA, Crowley J, Van Houtte P, Postmus PE, Carney D, Chansky K, Shaikh Z, Goldstraw P. 2007. 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.
    1. Sher F, Rossler R, Brouwer N, Balasubramaniyan V, Boddeke E, Copray S. 2008. Differentiation of neural stem cells into oligodendrocytes: involvement of the polycomb group protein Ezh2. Stem Cells 26: 2875–2883.
    1. Shivapurkar N, Virmani AK, Wistuba II, Milchgrub S, Mackay B, Minna JD, Gazdar AF. 1999. Deletions of chromosome 4 at multiple sites are frequent in malignant mesothelioma and small cell lung carcinoma. Clin Cancer Res 5: 17–23.
    1. Silva A, Wang J, Lomahan S, Tran TA, Grenlin L, Suganami A, Tamura Y, Ikegaki N. 2014. Aurora kinase A is a possible target of OSU03012 to destabilize MYC family proteins. Oncol Rep 32: 901–905.
    1. Snitow ME, Li S, Morley MP, Rathi K, Lu MM, Kadzik RS, Stewart KM, Morrisey EE. 2015. Ezh2 represses the basal cell lineage during lung endoderm development. Development 142: 108–117.
    1. Snyder A, Makarov V, Merghoub T, Yuan J, Zaretsky JM, Desrichard A, Walsh LA, Postow MA, Wong P, Ho TS, et al. 2014. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med 371: 2189–2199.
    1. Song H, Yao E, Lin C, Gacayan R, Chen M-H, Chuang P-T. 2012. Functional characterization of pulmonary neuroendocrine cells in lung development, injury, and tumorigenesis. Proc Natl Acad Sci 109: 17531–17536.
    1. Sos ML, Dietlein F, Peifer M, Schöttle J, Balke-Want H, Müller C, Koker M, Richters A, Heynck S, Malchers F, et al. 2012. A framework for identification of actionable cancer genome dependencies in small cell lung cancer. Proc Natl Acad Sci 109: 17034–17039.
    1. Spigel DR, Waterhouse DM, Lane S, Legenne P, Bhatt K. 2013. Efficacy and safety of oral topotecan and bevacizumab combination as second-line treatment for relapsed small-cell lung cancer: an open-label multicenter single-arm phase II study. Clin Lung Cancer 14: 356–363.
    1. Stevens TP, McBride JT, Peake JL, Pinkerton KE, Stripp BR. 1997. Cell proliferation contributes to PNEC hyperplasia after acute airway injury. Am J Physiol 272: L486–493.
    1. Stewart DJ. 2010. Tumor and host factors that may limit efficacy of chemotherapy in non-small cell and small cell lung cancer. Crit Rev Oncol Hematol 75: 173–234.
    1. Sun S-Y, Rosenberg LM, Wang X, Zhou Z, Yue P, Fu H, Khuri FR. 2005. Activation of Akt and eIF4E survival pathways by rapamycin-mediated mammalian target of rapamycin inhibition. Cancer Res 65: 7052–7058.
    1. Sutherland KD, Proost N, Brouns I, Adriaensen D, Song J-Y, Berns A. 2011. 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.
    1. Takahashi T, Nau MM, Chiba I, Birrer MJ, Rosenberg RK, Vinocour M, Levitt M, Pass H, Gazdar AF, Minna JD. 1989. p53: a frequent target for genetic abnormalities in lung cancer. Science 246: 491–494.
    1. Tan HL, Sood A, Rahimi HA, Wang W, Gupta N, Hicks J, Mosier S, Gocke CD, Epstein JI, Netto GJ, et al. 2014. Rb loss is characteristic of prostatic small cell neuroendocrine carcinoma. Clin Cancer Res 20: 890–903.
    1. Tannapfel A, John K, Mise N, Schmidt A, Buhlmann S, Ibrahim SM, Putzer BM. 2008. Autonomous growth and hepatocarcinogenesis in transgenic mice expressing the p53 family inhibitor DNp73. Carcinogenesis 29: 211–218.
    1. Tarhini A, Kotsakis A, Gooding W, Shuai Y, Petro D, Friedland D, Belani CP, Dacic S, Argiris A. 2010. Phase II study of everolimus (RAD001) in previously treated small cell lung cancer. Clin Cancer Res 16: 5900–5907.
    1. Toyooka S, Tsuda T, Gazdar AF. 2003. The TP53 gene, tobacco exposure, and lung cancer. Hum Mutat 21: 229–239.
    1. Umemura S, Mimaki S, Makinoshima H, Tada S, Ishii G, Ohmatsu H, Niho S, Yoh K, Matsumoto S, Takahashi A, et al. 2014. Therapeutic priority of the PI3K/AKT/mTOR pathway in small cell lung cancers as revealed by a comprehensive genomic analysis. J Thorac Oncol 9: 1324–1331.
    1. Van Lommel A. 2001. Pulmonary neuroendocrine cells (PNEC) and neuroepithelial bodies (NEB): chemoreceptors and regulators of lung development. Paediatr Respir Rev 2: 171–176.
    1. Van Lommel A, Bollé T, Fannes W, Lauweryns JM. 1999. The pulmonary neuroendocrine system: the past decade. Arch Histol Cytol 62: 1–16.
    1. van Meerbeeck JP, Fennell DA, De Ruysscher DKM. 2011. Small-cell lung cancer. Lancet 378: 1741–1755.
    1. Varjosalo M, Taipale J. 2008. Hedgehog: functions and mechanisms. Genes Dev 22: 2454–2472.
    1. Vaughan AE, Brumwell AN, Xi Y, Gotts JE, Brownfield DG, Treutlein B, Tan K, Tan V, Liu FC, Looney MR, et al. 2015. Lineage-negative progenitors mobilize to regenerate lung epithelium after major injury. Nature 517: 621–625.
    1. Vestergaard J, Pedersen MW, Pedersen N, Ensinger C, Tümer Z, Tommerup N, Poulsen HS, Larsen LA. 2006. Hedgehog signaling in small-cell lung cancer: frequent in vivo but a rare event in vitro. Lung Cancer 52: 281–290.
    1. Villaruz LC, Kalyan A, Zarour H, Socinski MA. 2014. Immunotherapy in lung cancer. Transl Lung Cancer Res 3: 2–14.
    1. Virmani AK, Fong KM, Kodagoda D, McIntire D, Hung J, Tonk V, Minna JD, Gazdar AF. 1998. Allelotyping demonstrates common and distinct patterns of chromosomal loss in human lung cancer types. Genes Chromosomes Cancer 21: 308–319.
    1. Wainberg ZA, Rafii S, Ramanathan RK, Mina L, Byers LA, Chugh R, Goldman JW, Sachdev JC, Matei DE, Wheler JJ, et al. 2014. Safety and antitumor activity of the PARP inhibitor BMN673 in a phase 1 trial recruiting metastatic small-cell lung cancer (SCLC) and germline BRCA-mutation carrier cancer patients. J Clin Oncol 32: 5s.
    1. Warshamana-Greene GS, Litz J, Buchdunger E, García-Echeverría C, Hofmann F, Krystal GW. 2005. The insulin-like growth factor-I receptor kinase inhibitor, NVP-ADW742, sensitizes small cell lung cancer cell lines to the effects of chemotherapy. Clin Cancer Res 11: 1563–1571.
    1. Watson WL, Berg JW. 1962. Oat cell lung cancer. Cancer 15: 759–768.
    1. Weinberg RA. 1995. The retinoblastoma protein and cell cycle control. Cell 81: 323–330.
    1. Westerman BA, Neijenhuis S, Poutsma A, Steenbergen RDM, Breuer RHJ, Egging M, van Wijk IJ, Oudejans CBM. 2002. Quantitative reverse transcription-polymerase chain reaction measurement of HASH1 (ASCL1), a marker for small cell lung carcinomas with neuroendocrine features. Clin Cancer Res 8: 1082–1086.
    1. Whiteman KR, Johnson HA, Mayo MF, Audette CA, Carrigan CN, LaBelle A, Zukerberg L, Lambert JM, Lutz RJ. 2014. Lorvotuzumab mertansine, a CD56-targeting antibody-drug conjugate with potent antitumor activity against small cell lung cancer in human xenograft models. MAbs 6: 556–566.
    1. Wikenheiser-Brokamp KA. 2004. Rb family proteins differentially regulate distinct cell lineages during epithelial development. Development 131: 4299–4310.
    1. Wistuba II, Behrens C, Virmani AK, Mele G, Milchgrub S, Girard L, Fondon JW, Garner HR, McKay B, Latif F, et al. 2000a. 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.
    1. Wistuba II, Berry J, Behrens C, Maitra A, Shivapurkar N, Milchgrub S, Mackay B, Minna JD, Gazdar AF. 2000b. Molecular changes in the bronchial epithelium of patients with small cell lung cancer. Clin Cancer Res 6: 2604–2610.
    1. Witschi H. 2001. A short history of lung cancer. Toxicol Sci 64: 4–6.
    1. Wojtalla A, Fischer B, Kotelevets N, Mauri FA, Sobek J, Rehrauer H, Wotzkow C, Tschan MP, Seckl MJ, Zangemeister-Wittke U, et al. 2013. Targeting the phosphoinositide 3-kinase p110-α isoform impairs cell proliferation, survival, and tumor growth in small cell lung cancer. Clin Cancer Res 19: 96–105.
    1. Wu C, Wangpaichitr M, Feun L, Kuo MT, Robles C, Lampidis T, Savaraj N. 2005. Overcoming cisplatin resistance by mTOR inhibitor in lung cancer. Mol Cancer 4: 25.
    1. Yazawa T, Kamma H, Fujiwara M, Matsui M, Horiguchi H, Satoh H, Fujimoto M, Yokoyama K, Ogata T. 1999. Lack of class II transactivator causes severe deficiency of HLA-DR expression in small cell lung cancer. J Pathol 187: 191–199.
    1. Yokomizo A, Tindall DJ, Drabkin H, Gemmill R, Franklin W, Yang P, Sugio K, Smith DI, Liu W. 1998. PTEN/MMAC1 mutations identified in small cell, but not in non-small cell lung cancers. Oncogene 17: 475–479.
    1. Zandi R, Selivanova G, Christensen CL, Gerds TA, Willumsen BM, Poulsen HS. 2011. PRIMA-1Met/APR-246 induces apoptosis and tumor growth delay in small cell lung cancer expressing mutant p53. Clin Cancer Res 17: 2830–2841.
    1. Zuber J, Shi J, Wang E, Rappaport AR, Herrmann H, Sison EA, Magoon D, Qi J, Blatt K, Wunderlich M, et al. 2011. RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia. Nature 478: 524–528.
    1. Zuo W, Zhang T, Wu DZ, Guan SP, Liew A-A, Yamamoto Y, Wang X, Lim SJ, Vincent M, Lessard M, et al. 2015. p63+Krt5+ distal airway stem cells are essential for lung regeneration. Nature 517: 616–620.

Source: PubMed

Patrocinadores y Colaboradores

Condiciones médicas

Intervenciones de drogas

3
Suscribir