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

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. Non-small-cell lung cancers (NSCLCs) are now appreciated to be a group of heterogeneous diseases. This Review discusses the biology of NSCLCs and what we know about their origins, diversity and the microenvironments surrounding them, with a view towards improving therapies. 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.