In pursuit of identifying mechanisms responsible for cross or “pan” resistance to agents that exploit replication stress, a recent study modeling acquired resistance using patient-derived models of SCLC found that MYC family paralog amplification via ecDNA drives acquired cross-resistance by amplifying replication stress response pathways and altering transcriptional landscapes.70,192 Recent evidence in mouse models from our groups suggests that the pulmonary NE cell can be transformed by the Myc oncogene alone, thus representing a fundamental oncogenic driver event. Here, MYC is linked to small cell lung carcinoma.