A PDX model combined with CD-DST assay to evaluate the antitumor properties of KRpep-2d and oxaliplatin in KRAS (G12D) mutant colorectal cancer.
A PDX model combined with CD-DST assay to evaluate the antitumor properties of KRpep-2d and oxaliplatin in KRAS (G12D) mutant colorectal cancer.
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DOI：
10.1016/j.heliyon.2022.e12518
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发表时间：
2022-12
期刊：
影响因子：
4
通讯作者：
Su, Qiao
中科院分区：
文献类型：
--
作者：
Li, Wuguo;Chen, Wei;Wang, Jialin;Zhao, Guangyin;Chen, Lianzhou;Wan, Yong;Luo, Qianxin;Li, Wenwen;Huang, Haoji;Li, Wenying;Li, Wu;Yang, Yutong;Chen, Daici;Su, Qiao
患者来源的异种移植(PDX)模型比细胞系模型更能保持人类肿瘤的特性，并被广泛应用于药物开发，但它们也存在一些缺点，如成功率相对较低，周转时间较长，成本较高。胶原胶微滴包埋培养药敏试验(CD-DST)以其原代细胞培养成功率高、敏感性高、临床实用性好等优点，已被应用于肿瘤患者的体外药敏试验，但它是建立在体外细胞培养的基础上的，不能准确模拟肿瘤微环境。本研究旨在将PDX模型与CD-DST相结合来评价抗肿瘤药物的有效性。针对KRAS(G12D)的小肽KRpep-2d和奥沙利铂验证了该方法的可行性。首次应用全外显子组测序和Sanger测序来检测和验证一组结直肠癌PDX组织的KRAS突变状态。其中一个PDX模型被证实携带KRAS(G12D)突变，并用于体内和CD-DST药物试验。然后，我们从带有KRAS(G12D)突变的患者身上建立了PDX小鼠模型，并从相同的PDX模型中获得了可存活的癌细胞。接下来，在PDX模型和CD-DST中评价KRpep-2d和奥沙利铂的抗肿瘤作用。我们发现KRpep-2d在异种移植模型或同一PDX模型来源的癌细胞上没有明显的抗肿瘤作用。相比之下，奥沙利铂在两种试验中都显示出显著的抑制作用。综上所述，PDX模型结合CD-DST分析是评价化合物抗肿瘤活性的一种全面可行的方法，可应用于新药开发。KRAS(G12D)；结直肠癌；KRPEP-2d；奥沙利铂；PDX模型；CD-DST；药物敏感性。
Patient-derived xenograft (PDX) models are more faithful in maintaining the characteristics of human tumors than cell lines and are widely used in drug development, although they have some disadvantages, including their relative low success rate, long turn-around time, and high costs. The collagen gel droplet embedded culture drug sensitivity test (CD-DST) has been used as an in-vitro drug sensitivity test for patients with cancer because of its high success rate of primary cell culture, high sensitivity, and good clinical relevance, but it is based on an in-vitro cell culture and may not simulate the tumor microenvironment accurately. This study aims to combine a PDX model with CD-DST to evaluate the efficiency of antitumor agents. KRpep-2d, a small peptide targeting KRAS (G12D), and oxaliplatin were used to verify the feasibility of this approach. Whole-exome sequencing and Sanger sequencing were first applied to test and validate the KRAS mutation status of a panel of colorectal cancer PDX tissues. One PDX model was verified to carry KRAS (G12D) mutation and was used for in-vivo and the CD-DST drug tests. We then established the PDX mouse model from the patient with the KRAS (G12D) mutation and obtained viable cancer cells derived from the same PDX model. Next, the antitumor abilities of KRpep-2d and oxaliplatin were estimated in the PDX model and the CD-DST. We found that KRpep-2d showed no significant antitumor effect on the xenograft model or on cancer cells derived from the same PDX model. In contrast, oxaliplatin showed significant inhibitory effects in both tests. In conclusion, the PDX model in combination with the CD-DST assay is a comprehensive and feasible method of evaluating the antitumor properties of compounds and could be applied for new drug discovery. KRAS (G12D); Colorectal cancer; KRpep-2d; Oxaliplatin; PDX model; CD-DST; Drug sensitivity.
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DOI：
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发表时间：
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期刊：
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影响因子：
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