Small cell lung cancer (SCLC) presents as a highly chemosensitive malignancy but acquires cross-resistance after relapse. This transformation is nearly inevitable in patients but has been difficult to capture in laboratory models. Here, we present a pre-clinical system that recapitulates acquired cross-resistance, developed from 51 patient-derived xenograft (PDX) models. Each model was tested in vivo against three clinical regimens: cisplatin plus etoposide, olaparib plus temozolomide, and topotecan. These drug-response profiles captured hallmark clinical features of SCLC, such as the emergence of treatment-refractory disease after early relapse. For one patient, serial PDX models revealed that cross-resistance was acquired through MYC amplification on extrachromosomal DNA (ecDNA). Genomic and transcriptional profiles of the full PDX panel revealed that MYC paralog amplifications on ecDNAs were recurrent in relapsed cross-resistant SCLC, and this was corroborated in tumor biopsies from relapsed patients. We conclude that ecDNAs with MYC paralogs are recurrent drivers of cross-resistance in SCLC.

中文翻译：

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由于 MYC 旁系同源物的染色体外 DNA 扩增，小细胞肺癌获得了交叉耐药性

小细胞肺癌（SCLC）是一种对化疗高度敏感的恶性肿瘤，但复发后会产生交叉耐药性。这种转变在患者中几乎是不可避免的，但很难在实验室模型中捕捉到。在这里，我们提出了一个临床前系统，该系统概括了获得性交叉耐药性，该系统由 51 个患者来源的异种移植 (PDX) 模型开发而成。每个模型都针对三种临床方案进行了体内测试：顺铂加依托泊苷、奥拉帕尼加替莫唑胺和托泊替康。这些药物反应概况捕捉了 SCLC 的标志性临床特征，例如早期复发后出现治疗难治性疾病。对于一名患者，系列 PDX 模型显示交叉耐药性是通过染色体外 DNA (ecDNA) 上的 MYC 扩增获得的。完整 PDX 组合的基因组和转录谱显示，ecDNA 上的 MYC 旁系同源扩增在复发性交叉耐药 SCLC 中反复出现，这在复发患者的肿瘤活检中得到了证实。我们得出的结论是，具有 MYC 旁系同源物的 ecDNA 是 SCLC 交叉耐药的反复驱动因素。