A PDX model combined with CD-DST assay to evaluate the antitumor properties of KRpep-2d and oxaliplatin in KRAS (G12D) mutant colorectal cancer

by Selleckchem | Aug 06 2023

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.

Comments:

The study aimed to assess the effectiveness of combining patient-derived xenograft (PDX) models with the collagen gel droplet embedded culture drug sensitivity test (CD-DST) for evaluating the efficiency of antitumor agents. The researchers focused on testing the feasibility of KRpep-2d, a small peptide targeting KRAS (G12D), and oxaliplatin as potential antitumor agents.

The study initially utilized whole-exome sequencing and Sanger sequencing to validate the KRAS mutation status of a panel of colorectal cancer PDX tissues. One PDX model with the KRAS (G12D) mutation was identified and selected for subsequent in-vivo and CD-DST drug tests. The researchers established a PDX mouse model using cancer cells derived from the same PDX model.

The antitumor properties of KRpep-2d and oxaliplatin were then evaluated using both the PDX model and the CD-DST assay. However, the results indicated that KRpep-2d did not demonstrate a significant antitumor effect on either the xenograft model or the cancer cells derived from the PDX model. On the other hand, oxaliplatin exhibited significant inhibitory effects in both tests.

In conclusion, the study suggests that the combination of PDX models and CD-DST can serve as a comprehensive and feasible method for evaluating the antitumor properties of compounds. This approach holds potential for application in new drug discovery efforts. However, in this specific study, KRpep-2d did not exhibit significant antitumor effects, while oxaliplatin demonstrated notable inhibitory effects in both the PDX model and the CD-DST assay.