Purpose: To investigate the molecular characteristics of and potential for precision medicine in KRAS wildtype pancreatic ductal adenocarcinoma (PDAC). Patients and Methods: We investigated 27 patients withKRASWTPDAC at our institution. Clinical data were obtained via chart review. Tumor specimens for each subject were interrogated for somatic single nucleotide variants, insertion and deletions, and copy number variants by DNA sequencing. Gene fusions were detected from RNA-seq. A patient-derived organoid (PDO) was developed from a patient with aMETtranslocation and expanded ex vivo to predict therapeutic sensitivity prior to enrollment in a phase 2 clinical trial. Results: Transcriptomic analysis showed our cohort may be stratified by the relative gene expression of the KRAS signaling cascade. The PDO derived from our patient harboring aTFG-METrearrangement was found to have in vitro sensitivity to the multi-tyrosine kinase inhibitor crizotinib. The patient was enrolled in the phase 2 SPARTA clinical trial and received monotherapy with vebrelitinib, a c-MET inhibitor, and achieved a partial and durable response. Conclusions:KRASWTPDAC is molecularly distinct fromKRASMUTand enriched with potentially actionable genetic variants. In our study, transcriptomic profiling revealed that the KRAS signaling cascade may play a key role inKRASWTPDAC. Our report of aKRASWTPDAC patient with TFG-MET rearrangement who responded to a cMET inhibitor further supports the pursuit of precision oncology in this sub-population. Identification of targetable mutations, perhaps through approaches like RNA-seq, can help enable precision-driven approaches to select optimal treatment based on tumor characteristics.
目的：探讨KRAS野生型胰腺导管腺癌（PDAC）的分子特征及其在精准医疗中的潜力。患者与方法：本研究纳入我院27例KRAS野生型PDAC患者。通过病历回顾获取临床资料。对每位患者的肿瘤样本进行DNA测序，检测体细胞单核苷酸变异、插入缺失及拷贝数变异。通过RNA测序检测基因融合。从携带MET易位的患者体内构建患者来源类器官（PDO），并在体外扩增，用于在患者入组II期临床试验前预测治疗敏感性。结果：转录组分析显示，本研究队列可根据KRAS信号通路的相对基因表达进行分层。从携带TFG-MET重排的患者构建的PDO在体外显示出对多酪氨酸激酶抑制剂克唑替尼的敏感性。该患者入组II期SPARTA临床试验，接受c-MET抑制剂vebrelitinib单药治疗，并获得部分且持久的缓解。结论：KRAS野生型PDAC在分子水平上与KRAS突变型存在显著差异，且富含潜在可干预的遗传变异。本研究中，转录组分析揭示KRAS信号通路可能在KRAS野生型PDAC中发挥关键作用。我们报道了一例携带TFG-MET重排的KRAS野生型PDAC患者对c-MET抑制剂产生应答，进一步支持在该亚群中推进精准肿瘤学实践。通过RNA测序等方法识别可靶向突变，有助于实现基于肿瘤特征的精准医疗策略，从而选择最佳治疗方案。
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