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

中文翻译：

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MYCN 驱动小细胞肺癌的化疗耐药性，而 USP7 抑制可以恢复化疗敏感性。

小细胞肺癌（SCLC）是一种侵袭性神经内分泌癌，其特征是最初对化疗敏感，随后出现化疗耐药性疾病。为了研究MYCN扩增在 SCLC 进展和化疗耐药中的作用，我们开发了MYCN过表达 SCLC的基因工程小鼠模型。在未经治疗的小鼠中，MYCN过度表达促进细胞周期进展，抑制细胞毒性 T 细胞的浸润，并加速 SCLC。MYCN过表达也抑制对顺铂-依托泊苷化疗的反应，与MYCL过表达相似的结果。我们将这些数据扩展到对化学敏感的 SCLC 异种移植 (PDX) 模型进行遗传干扰。在化学敏感的 PDX 模型中，MYCN或MYCL的过度表达也会导致化学耐药性的转变。为了确定MYCN过度表达 SCLC的治疗策略，我们进行了基因组规模的 CRISPR-Cas9 sgRNA 筛选。我们将去泛素酶 USP7 确定为MYCN相关的合成漏洞。USP7 的药理学抑制使化疗耐药的MYCN过表达 PDX 模型对体内化疗重新敏感。我们的研究结果表明，MYCN过表达会导致 SCLC 化疗耐药，并提供恢复化疗敏感性的治疗策略。