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Non-small-cell lung cancers: a heterogeneous set of diseases

A Corrigendum to this article was published on 19 March 2015

This article has been updated

Key Points

  • Next-generation sequencing and other high-throughput analyses have begun to show the many different molecular and genetic subsets of non-small-cell lung cancer (NSCLC) and have drastically altered the clinical evaluation and treatment of patients during the past decade.

  • The pathological features and treatment response of NSCLC are affected by genetic and epigenetic profiles, as well as by the cellular origins of the tumours.

  • Target-specific small-molecule inhibitors, such as epidermal growth factor receptor (EGFR) and echinoderm microtubule-associated protein-like 4 (EML4)–anaplastic lymphoma kinase (ALK) inhibitors, have achieved much greater treatment response and survival advantage compared with conventional chemotherapies. However, the treatment response is often short-lived and survival remains limited.

  • Cellular heterogeneity within the tumour milieu influences tumorigenesis, tumour progression and treatment response. The main components of this dynamic microenvironment include vasculature, immune cells, fibroblasts and tumour cell subpopulations.

  • Immune therapies that aim to rejuvenate antitumour immune responses have shown success in early clinical trials. The combination of immunotherapy with other targeted therapies is anticipated in the near future.

  • Data from the bench on criteria for patient stratification and treatment selection are increasingly being translated into clinical practice.

Abstract

Non-small-cell lung cancers (NSCLCs), the most common lung cancers, are known to have diverse pathological features. During the past decade, in-depth analyses of lung cancer genomes and signalling pathways have further defined NSCLCs as a group of distinct diseases with genetic and cellular heterogeneity. Consequently, an impressive list of potential therapeutic targets was unveiled, drastically altering the clinical evaluation and treatment of patients. Many targeted therapies have been developed with compelling clinical proofs of concept; however, treatment responses are typically short-lived. Further studies of the tumour microenvironment have uncovered new possible avenues to control this deadly disease, including immunotherapy.

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Figure 1: The lung cancer microenvironment.
Figure 2: A diagram of proximal and distal lung cells, indicating markers that are retained in carcinomas and putative squamous cell carcinoma (SCC) and adenocarcinoma (ADC) cells of origin.

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Change history

  • 19 March 2015

    In the original version of this article, the word 'proximal' was incorrectly used twice instead of 'distal' in two sentences in the legend for Figure 2. The sentences should have stated "ADCs can be modelled by KrasG12D expression (long latency), KrasG12D expression and Trp53-null, and epidermal growth factor receptor (EGFR)T790M/L858R, among other genetic models, and they are thought to arise from more distal airway cells. These tumours often retain characteristics of distal airways, such as the expression of surfactant protein C (SPC), KRT7 and thyroid transcription factor 1 (TTF1)." These corrections have been made in the online version of the article.

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Acknowledgements

The authors thank United Against Lung Cancer, Thoracic Foundation, Bonnie J Addario Lung Cancer Foundation, Claudia Adams Barr Program For Basic Cancer Research, grant numbers CA122794, CA166480, CA163896, CA154303, CA120964 CA140594.

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Correspondence to Peter S. Hammerman, Carla F. Kim or Kwok-Kin Wong.

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Glossary

Myeloid-derived suppressor cells

(MDSCs). MDSCs encompass a heterogeneous population of myeloid cells, which share the ability to suppress T cells through the production of arginase and the expression of inducible nitric oxide synthase (iNOS).

Pseudostratified epithelium

This describes the epithelium of the trachea, which is truly a monolayer but appears to have some stratification due to the variable distances of the nuclei from the basal lamina.

Patient-derived xenograft

(PDX). Primary tumour cells from fresh patient tumours that are propagated subcutaneously in immunocompromised mice.

EGFR-T790M

The most common mutation (50%) in the epidermal growth factor receptor (EGFR) gene that confers resistance to EGFR tyrosine kinase inhibitors such as erlotinib and gefitinib.

Cytotoxic T lymphocyte protein 4

(CTLA4; also known as CD152). A surface receptor that transmits inhibitory signals to T cells.

CD73

A cell surface enzyme that generates extracellular adenosine, which inhibits T cell function.

CD47

The receptor for thrombospondin 1 (TSP1). CD47 is highly expressed in many tumour cells.

Chimeric antigen receptors

(CARs). Genetically engineered receptors that result in desired specificity (to tumour cells) in effector T cells.

CpG island methylator phenotype

(CIMP). Reflects the genomic status that multiple CpG islands are methylated simultaneously, leading to epigenetic inactivation of different genes, including tumour suppressors.

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Chen, Z., Fillmore, C., Hammerman, P. et al. Non-small-cell lung cancers: a heterogeneous set of diseases. Nat Rev Cancer 14, 535–546 (2014). https://doi.org/10.1038/nrc3775

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