Lee Carol, Mu Weixue, Chen Xi July, Chan Mandy Sze Man, Chen Zhishan, Yeung Sai Fung, Chan Helen Hoi Yin, Chow Sin Ting, Ko Ben Chi Bun, Chan David Wai, Cho William C, Lui Vivian Wai Yan, Tsui Stephen Kwok Wing
School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong.
Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong.
Cancers (Basel). 2025 Jul 4;17(13):2246. doi: 10.3390/cancers17132246.
: RAF pathway aberrations are one of the hallmarks of lung cancer. Sorafenib is a multi-kinase inhibitor targeting the RAF pathway and is FDA-approved for several cancers, yet its efficacy in lung cancer is controversial. Previous clinical research showed that a p.S214C mutation exhibited exceptional responsiveness to sorafenib in lung adenocarcinoma. : Considering this promising clinical potential, the oncogenic potential and sorafenib response of the p.S214C mutation were investigated using lung cancer models. p.S214C mutant, wild-type (WT), and control genes were ectopically expressed in lung adenocarcinoma cell lines retroviral transduction. In vitro and in vivo sorafenib sensitivity studies were performed, followed by transcriptomics and proteomics analyses. : Compared to the -WT and -engineered cells, the p.S214C-engineered cells activated Raf-MEK-ERK signaling and exhibited enhanced oncogenic potential in terms of in vitro cell proliferation, colony and spheroid formation, migration, and invasion abilities, as well as in vivo tumorigenicity. The p.S214C-engineered cells also displayed heightened sensitivity to sorafenib in vitro and in vivo. RNA sequencing and reverse-phase protein array analyses demonstrated elevated expression of genes and proteins associated with tumor aggressiveness in the p.S214C mutants, and its sorafenib sensitivity was likely moderated through inhibition of the cell cycle and DNA replication. The ERK and PI3K signaling pathways were also significantly deregulated in the p.S214C mutants regardless of sorafenib treatment. : This study demonstrates the oncogenicity and sorafenib sensitivity of the p.S214C mutation in lung cancer cells, which may serve as a biomarker for predicting the sorafenib response in lung cancer patients. Importantly, investigating the gene-drug sensitivity pairs in clinically exceptional responders may guide and accelerate personalized cancer therapies based on specific tumor mutations.
RAF信号通路异常是肺癌的特征之一。索拉非尼是一种靶向RAF信号通路的多激酶抑制剂，已获美国食品药品监督管理局（FDA）批准用于多种癌症，但它在肺癌中的疗效存在争议。先前的临床研究表明，p.S214C突变在肺腺癌中对索拉非尼表现出异常的反应性。考虑到这种有前景的临床潜力，利用肺癌模型研究了p.S214C突变的致癌潜力和对索拉非尼的反应。通过逆转录病毒转导在肺腺癌细胞系中异位表达p.S214C突变体、野生型（WT）和对照基因。进行了体外和体内索拉非尼敏感性研究，随后进行了转录组学和蛋白质组学分析。与WT和工程改造细胞相比，p.S214C工程改造细胞激活了Raf-MEK-ERK信号通路，在体外细胞增殖、集落和球体形成、迁移和侵袭能力以及体内致瘤性方面表现出增强的致癌潜力。p.S214C工程改造细胞在体外和体内对索拉非尼也表现出更高的敏感性。RNA测序和反相蛋白质阵列分析表明，p.S214C突变体中与肿瘤侵袭性相关的基因和蛋白质表达升高，其对索拉非尼的敏感性可能通过抑制细胞周期和DNA复制来调节。无论是否进行索拉非尼治疗，p.S214C突变体中的ERK和PI3K信号通路也明显失调。这项研究证明了p.S214C突变在肺癌细胞中的致癌性和对索拉非尼的敏感性，这可能作为预测肺癌患者对索拉非尼反应的生物标志物。重要的是，研究临床特殊反应者中的基因-药物敏感性配对可能会指导并加速基于特定肿瘤突变的个性化癌症治疗。
