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

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.

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.