The natural history of small-cell lung cancer (SCLC) includes rapid evolution from chemosensitivity to chemoresistance, although mechanisms underlying this evolution remain obscure due to the scarcity of post-relapse tissue samples. We generated circulating tumor cell (CTC)-derived xenografts from patients with SCLC to study intratumoral heterogeneity (ITH) via single-cell RNA sequencing of chemosensitive and chemoresistant CTC-derived xenografts and patient CTCs. We found globally increased ITH, including heterogeneous expression of therapeutic targets and potential resistance pathways, such as epithelial-to-mesenchymal transition, between cellular subpopulations following treatment resistance. Similarly, serial profiling of patient CTCs directly from blood confirmed increased ITH post-relapse. These findings suggest that treatment resistance in SCLC is characterized by coexisting subpopulations of cells with heterogeneous gene expression leading to multiple, concurrent resistance mechanisms. These findings emphasize the need for clinical efforts to focus on rational combination therapies for treatment-naïve SCLC tumors to maximize initial responses and counteract the emergence of ITH and diverse resistance mechanisms.

小细胞肺癌（SCLC）的自然史包括从化疗敏感性到化疗耐药性的快速演变，尽管由于复发后组织样本的稀缺，这种演变的机制仍然不清楚。我们从 SCLC 患者身上生成了循环肿瘤细胞 (CTC) 衍生的异种移植物，通过对化疗敏感和化疗耐药的 CTC 衍生异种移植物和患者 CTC 进行单细胞 RNA 测序来研究瘤内异质性 (ITH)。我们发现全球 ITH 增加，包括治疗靶点的异质表达和潜在耐药途径，例如治疗耐药后细胞亚群之间的上皮间质转化。同样，直接从血液中对患者 CTC 进行连续分析证实了复发后 ITH 增加。这些发现表明，SCLC 的治疗耐药性的特点是具有异质基因表达的细胞亚群共存，导致多种并发耐药机制。这些发现强调，临床工作需要重点关注针对初治 SCLC 肿瘤的合理联合疗法，以最大限度地提高初始反应并抵消 ITH 和多种耐药机制的出现。