Lung cancer is the leading cause of cancer-related deaths with small-cell lung cancer (SCLC) as the most aggressive subtype. Preferential occurrence of TP53 missense mutations rather than loss implicates a selective advantage for TP53-mutant expression in SCLC pathogenesis. We show that lung epithelial expression of R270H and R172H (R273H and R175H in humans), common TRP53 mutants in lung cancer, combined with RB1 loss selectively results in two subtypes of neuroendocrine carcinoma, SCLC and large cell neuroendocrine carcinoma (LCNEC). Tumor initiation and progression occur in a remarkably consistent time frame with short latency and uniform progression to lethal metastatic disease by 7 months. R270H or R172H expression and TRP53 loss result in similar phenotypes demonstrating that TRP53 mutants promote lung carcinogenesis through loss-of-function and not gain-of-function mechanisms. Tumor responses to targeted and cytotoxic therapeutics were discordant in mice and corresponding tumor cell cultures demonstrating need to assess therapeutic response at the organismal level. Rapamycin did not have therapeutic efficacy in the mouse model despite inhibiting mTOR signaling and markedly suppressing tumor cell growth in culture. In contrast, cisplatin/etoposide treatment using a patient regimen prolonged survival with development of chemoresistance recapitulating human responses. R270H, but not R172H, expression conferred gain-of-function activity in attenuating chemotherapeutic efficacy. These data demonstrate a causative role for TRP53 mutants in development of chemoresistant lung cancer, and provide tractable preclinical models to test novel therapeutics for refractory disease. Mol Cancer Ther; 16(12); 2913–26. ©2017 AACR.

中文翻译：

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Trp53 突变体通过功能丧失机制驱动神经内分泌肺癌，对化疗反应具有功能获得效应

肺癌是癌症相关死亡的主要原因，小细胞肺癌 (SCLC) 是最具侵袭性的亚型。TP53 错义突变的优先发生而不是丢失意味着 TP53 突变体表达在 SCLC 发病机制中具有选择性优势。我们表明，肺癌中常见的 TRP53 突变体 R270H 和 R172H（人类中的 R273H 和 R175H）的肺上皮表达，结合 RB1 丢失选择性地导致神经内分泌癌的两种亚型，SCLC 和大细胞神经内分泌癌 (LCNEC)。肿瘤的发生和进展发生在非常一致的时间范围内，潜伏期短，并且在 7 个月时统一进展为致命的转移性疾病。R270H 或 R172H 表达和 TRP53 丢失导致相似​​的表型，表明 TRP53 突变体通过功能丧失而不是功能获得机制促进肺癌发生。肿瘤对靶向治疗和细胞毒性治疗的反应在小鼠和相应的肿瘤细胞培养物中不一致，表明需要在生物体水平评估治疗反应。尽管雷帕霉素抑制了 mTOR 信号传导并显着抑制了培养物中的肿瘤细胞生长，但在小鼠模型中没有治疗功效。相比之下，使用患者方案的顺铂/依托泊苷治疗延长了生存期，并产生了概括人类反应的化学抗性。R270H，但不是 R172H，表达在减弱化疗功效方面赋予功能获得活性。这些数据证明了 TRP53 突变体在化学抗性肺癌的发展中的致病作用，并提供了易于处理的临床前模型来测试针对难治性疾病的新疗法。摩尔癌症治疗; 16(12); 2913-26。©2017 AACR。