<i>MYCN</i> drives chemoresistance in small cell lung cancer while USP7 inhibition can restore chemosensitivity

Small cell lung cancer (SCLC) is an aggressive neuroendocrine cancer characterized by initial chemosensitivity followed by emergence of chemoresistant disease. To study roles for <i>MYCN</i> amplification in SCLC progression and chemoresistance, we developed a genetically engineered mouse model of <i>MYCN</i>-overexpressing SCLC. In treatment-naïve mice, <i>MYCN</i> overexpression promoted cell cycle progression, suppressed infiltration of cytotoxic T cells, and accelerated SCLC. <i>MYCN</i> overexpression also suppressed response to cisplatin-etoposide chemotherapy, with similar findings made upon <i>MYCL</i> overexpression. We extended these data to genetically perturb chemosensitive patient-derived xenograft (PDX) models of SCLC. In chemosensitive PDX models, overexpression of either <i>MYCN</i> or <i>MYCL</i> also conferred a switch to chemoresistance. To identify therapeutic strategies for <i>MYCN</i>-overexpressing SCLC, we performed a genome-scale CRISPR-Cas9 sgRNA screen. We identified the deubiquitinase USP7 as a <i>MYCN</i>-associated synthetic vulnerability. Pharmacological inhibition of USP7 resensitized chemoresistant <i>MYCN</i>-overexpressing PDX models to chemotherapy in vivo. Our findings show that <i>MYCN</i> overexpression drives SCLC chemoresistance and provide a therapeutic strategy to restore chemosensitivity.