Transcriptional deregulation underlying the pathogenesis of small cell lung cancer

Small cell lung cancer (SCLC) is one of the few cancers for which mutations in transcription regulators, namely RB and P53, are a primary genetic cause. Genomic analyses of patient SCLC tumors revealed that a majority of recurrent somatic alterations affect transcription factors and chromatin modifiers including members of MYC family, SOX2, MLL1/2, CREBBP-EP300, RBL2, and P73. Frequent alterations in these proteins indicate that transcriptional deregulation beyond the loss of RB and P53 underlies cellular transformation and malignant progression of SCLC, causing aberrant expression of a broad range of genes related to cell proliferation and growth signaling pathways. As the concept of targeting chromatic modifiers including BRD4 using small molecule inhibitors have recently emerged for SCLC, characterization of the deregulated transcription programs is critical for discovery of potential targets and defining mechanism of targeted therapy. Recent integrated approaches using functional genomics and genetics and advanced mouse models have enabled interrogation of aberrant transcription program during SCLC development, identifying key oncogenic drivers and their mechanisms of action and conducting preclinical studies involving targeting transcriptional alterations. This review summarizes recent progresses in our understanding of transcriptional deregulation in SCLC development and tumor heterogeneity