PO.ET03.08 · 实验与分子治疗
实时解析KRAS G12C LUAD肿瘤中SCLC的出现：靶向治疗耐药的案例研究
Real-time dissection of SCLC emergence in a KRAS G12C LUAD tumour: A case study of targeted therapy resistance
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：谱系可塑性是非小细胞肺癌（NSCLC）中一种新兴的耐药机制。我们呈现一例KRAS G12C突变型肺腺癌（LUAD）PDX的案例研究，该PDX在接受KRAS G12C抑制剂sotorasib治疗后经历了向小细胞肺癌（SCLC）的神经内分泌转分化。
方法：用sotorasib处理KRAS G12C PDX CBX336，并使用高内涵成像、荧光谱系追踪、DNA条形码和全外显子克隆追踪进行监测。治疗前后的肿瘤接受了基因组、转录组和形态测量分析。PDX来源的离体培养支持功能研究，包括CRISPR敲除和cDNA过表达。
结果：CBX336对sotorasib显示出初始应答，随后迅速再生长。治疗后样本表现出从LUAD到SCLC的组织学转变，以NEUROD1和神经内分泌标志物升高为特征。谱系追踪揭示了一个协调的、而非随机的向神经内分泌状态的转变。多组学分析将ZEB1识别为与RB1缺失、p16升高和N-钙黏蛋白相关的上游调控因子。ZEB1敲除抑制了神经内分泌标志物的诱导并部分恢复了LUAD样分化，证实ZEB1是谱系重编程的驱动因素。
结论：本案例研究表明，KRAS G12C靶向治疗可通过ZEB1上调诱导神经内分泌转分化。对CBX336进化的实时监测揭示了可干预的可塑性机制，并支持开发预防或逆转治疗诱导的SCLC出现的策略。
查看英文原文 English abstract
Background: Lineage plasticity is an emerging mechanism of resistance in non-small cell lung cancer (NSCLC). We present a case study of a KRASG12C-mutant lung adenocarcinoma (LUAD) PDX that underwent neuroendocrine transdifferentiation into small-cell lung cancer (SCLC) after treatment with the KRASG12C inhibitor sotorasib.
Methods: KRASG12C PDX CBX336 was treated with sotorasib and monitored using high-content imaging, fluorescence lineage tracking, DNA barcoding, and whole-exome clonal tracing. Pre- and post-treatment tumours underwent genomic, transcriptomic, and morphometric profiling. PDX-derived ex vivo cultures supported functional studies, including CRISPR knockout and cDNA overexpression.
Results: CBX336 showed an initial response to sotorasib followed by rapid regrowth. Post-treatment samples demonstrated a histologic shift from LUAD to SCLC, marked by elevated NEUROD1 and neuroendocrine markers. Lineage tracking revealed a coordinated, not stochastic, transition toward the neuroendocrine state. Multi-omic analysis identified ZEB1 as an upstream regulator linked to RB1 loss, increased p16, and N-cadherin. ZEB1 knockout suppressed neuroendocrine marker induction and partially restored LUAD-like differentiation, confirming ZEB1 as a driver of lineage reprogramming.
Conclusions: This case study shows that KRASG12C-targeted therapy can induce neuroendocrine transdifferentiation via ZEB1 upregulation. Real-time monitoring of CBX336 evolution reveals actionable plasticity mechanisms and supports development of strategies to prevent or reverse therapy-induced SCLC emergence.
利益披露 Disclosure
P. Gopal, None.