SUMMARY 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 potential targeted treatment approach for MYC-driven SCLC.

Highlights d Multiple SCLC molecular subtypes arise from a neuroendocrine cell of origin d MYC drives the NEUROD1 + and YAP1 + subtypes of SCLC in a temporal evolution d MYC directly activates NOTCH signaling to reprogram neuroendocrine fate d Multiple SCLC molecular subtypes are present within individual human tumors

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