Family matters: How MYC family oncogenes impact small cell lung cancer

Abstract

Small cell lung cancer (SCLC) is one of the most deadly cancers and currently lacks effective targeted treatment options. Recent advances in the molecular characterization of SCLC has provided novel insight into the biology of this disease and raises hope for a paradigm shift in the treatment of SCLC. We and others have identified activation of MYC as a driver of susceptibility to Aurora kinase inhibition in SCLC cells and tumors that translates into a therapeutic option for the targeted treatment of MYC-driven SCLC. While MYC shares major features with its paralogs MYCN and MYCL, the sensitivity to Aurora kinase inhibitors is unique for MYC-driven SCLC. In this review, we will compare the distinct molecular features of the 3 MYC family members and address the potential implications for targeted therapy of SCLC.

Keywords: GEMM; MYC; MYCL; MYCN; SCLC; mouse models; small cell lung cancer.

Figure 1.

Schematic overview of major characteristics of the 3 MYC family paralogs with a focus on SCLC. Rows 1–3: Biochemical properties and physiological functions of MYC family members- protein domain architecture, phenotype of knockout mouse models and predominant distribution of MYC family member expression across tissues (broad expression of MYC, expression of MYCN primarily in neural and neuroendocrine tissues, and MYCL expression mainly in the lung). Row 4: Response of SCLC models to Aurora kinase inhibition with high sensitivity of MYC amplified/overexpressing cells. Row 5: Schematic differences of SCLC mouse models regarding genetic background, MYC family member activity/alteration and expression of neuroendocrine markers including the transcription factors Neurod1 and Ascl1. (bHLH = basic Helix-Loop-Helix, NLS = nuclear localization sequence, GEM = genetically engineered mouse, NE = neuroendocrine).