Desai Aakash, Xiao Alexander H, Choi Daheui, Toruner Merih D, Walden Daniel, Halfdanarson Thorvardur R, Alberts Steven, McWilliams Robert R, Mahipal Amit, Ahn Daniel, Babiker Hani, Stybayeva Gulnaz, Revzin Alexander, Kizilbash Sani, Adjei Alex, Bekaii-Saab Tanios, Mansfield Aaron S, Carr Ryan M, Ma Wen Wee
Department of Oncology, Mayo Clinic, Rochester, MN 55902, USA.
Department of Medicine, Mayo Clinic, Rochester, MN 55902, USA.
Cancers (Basel). 2024 May 13;16(10):1861. doi: 10.3390/cancers16101861.
To investigate the molecular characteristics of and potential for precision medicine in KRAS wildtype pancreatic ductal adenocarcinoma (PDAC).
We investigated 27 patients with PDAC 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 a translocation and expanded ex vivo to predict therapeutic sensitivity prior to enrollment in a phase 2 clinical trial.
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 a rearrangement 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.
PDAC is molecularly distinct from and enriched with potentially actionable genetic variants. In our study, transcriptomic profiling revealed that the KRAS signaling cascade may play a key role in PDAC. Our report of a PDAC 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.
研究KRAS野生型胰腺导管腺癌（PDAC）的分子特征及精准医疗潜力。
我们对本机构的27例PDAC患者进行了研究。通过查阅病历获取临床数据。采用DNA测序对每个受试者的肿瘤标本进行体细胞单核苷酸变异、插入和缺失以及拷贝数变异检测。从RNA测序中检测基因融合情况。从一名发生易位的患者身上培养出患者来源的类器官（PDO），并在体外进行扩增，以在入组2期临床试验前预测治疗敏感性。
转录组分析表明，我们的队列可根据KRAS信号级联的相对基因表达进行分层。发现我们培养的携带重排的患者来源的PDO对多酪氨酸激酶抑制剂克唑替尼具有体外敏感性。该患者入组了2期SPARTA临床试验，接受了c-MET抑制剂维布瑞替尼单药治疗，并取得了部分且持久的缓解。
PDAC在分子水平上有别于其他肿瘤，且富含潜在可操作的基因变异。在我们的研究中，转录组分析显示KRAS信号级联可能在PDAC中起关键作用。我们报告的一名发生TFG-MET重排的PDAC患者对c-MET抑制剂有反应，这进一步支持了在这一亚组人群中开展精准肿瘤学研究。通过RNA测序等方法识别可靶向的突变，有助于基于肿瘤特征采用精准驱动的方法来选择最佳治疗方案。
