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.Lung cancer results in the largest number of cancer-related deaths worldwide 1,2 . More than 85% of those cases are currently classified as non-small-cell lung cancer (NSCLC), for which the predicted 5-year survival rate is 15.9% -a figure that has only marginally improved during the past few decades 3 . Technological advances during the past decade, including the introduction of next-generation sequencing (NGS), the generation of multiple genetically engineered mouse models (GEMMs) of lung cancer and the construction of large databases characterizing the molecular features of human tumours, have transformed our view of NSCLC from histopathological descriptions to precise molecular and genetic identities that can be resolved to the single-cell level. In parallel, approaches and concepts from fields such as developmental biology, stem cell biology and immunology have deepened our knowledge of tumour development, cellular heterogeneity and interactions between the lung tumour and its surrounding microenvironment. These multidisciplinary Correspondence to P.S.H., C.F.K. and K.-K.W. phammerman@partners.org; carla.kim@childrens.harvard.edu; kwong1@partners.org. * These authors contributed equally to this work.
Competing interests statementThe authors declare no competing interests.
HHS Public AccessAuthor manuscript Nat Rev Cancer. Author manuscript; available in PMC 2017 December 04.
Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript efforts have enhanced our understanding of molecular disease mechanisms, thereby forming the rationales for targeting different cellular compartments simultaneously. Scientists and physicians have better tools than ever to pursue answers to two provocative questions: first, how can we define the specific subsets of NSCLC that differ by cellular and molecular composition? Second, how can we effectively control lung cancer growth for each specific subset of NSCLC? In this Review, we discuss how data that are derived from technological advances in lung cancer genomics, mouse modelling of cancers and tumour microenvironment studies might be used to improve the survival of patients with NSCLC through the development of novel therapeutic strategies.
Defining NSCLC subsetsNSCLC is currently defined by pathological characteristics. The two...