MYC Drives Progression of Small Cell Lung Cancer to a Variant Neuroendocrine Subtype with Vulnerability to Aurora Kinase Inhibition

Loss of the tumor suppressors RB1 and TP53 and MYC amplification are frequent oncogenic events in small cell lung cancer (SCLC). We show that Myc expression cooperates with Rb1 and Trp53 loss in the mouse lung to promote aggressive, highly metastatic tumors, that are initially sensitive to chemotherapy followed by relapse, similar to human SCLC. Importantly, MYC drives a neuroendocrine-low “variant” subset of SCLC with high NEUROD1 expression corresponding to transcriptional profiles of human SCLC. Targeted drug screening reveals that SCLC with high MYC expression is vulnerable to Aurora kinase inhibition, which combined with chemotherapy strongly suppresses tumor progression and increases survival. These data identify molecular features for patient stratification and uncover a novel targeted treatment approach for MYC-driven SCLC.EGA study EGAS00001002115

肿瘤抑制基因RB1与TP53的缺失以及MYC扩增，是小细胞肺癌（Small Cell Lung Cancer, SCLC）中常见的致癌事件。本研究证实，小鼠肺部中Myc的表达与Rb1及Trp53缺失协同作用，可诱导形成侵袭性强、高转移性的肿瘤；此类肿瘤初始对化疗敏感，随后会出现复发，与人类小细胞肺癌的病程高度相似。尤为关键的是，MYC可驱动一类神经内分泌低表达的“变异型”小细胞肺癌亚群，该亚群高表达NEUROD1，其转录谱与人类小细胞肺癌的转录特征相符。靶向药物筛选实验显示，高表达MYC的小细胞肺癌对极光激酶（Aurora kinase）抑制疗法敏感，该疗法联合化疗可显著抑制肿瘤进展并提升生存率。本研究数据明确了可用于患者分层的分子特征，并为MYC驱动型小细胞肺癌找到了全新的靶向治疗策略。EGA研究 EGAS00001002115