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

A Corrigendum to this article was published on 01 December 2017

This article has been updated

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.

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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.

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Change history

  • 10 November 2017

    There were errors in two sentences within the section ‘Epigenetic changes in SCLC’, indicating that EZH2 suppresses ASCL1 expression by suppression of TGFβ signalling. Instead, EZH2 promotes ASCL1 expression by suppression of TGFβ signalling. This has been corrected in the online and print versions of the article.

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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.).

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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.

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Correspondence to Adi F. Gazdar.

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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.

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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.

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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). https://doi.org/10.1038/nrc.2017.87

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