A PDX model combined with CD-DST assay to evaluate the antitumor properties of KRpep-2d and oxaliplatin in KRAS (G12D) mutant colorectal cancer
Wuguo Li,
Wei Chen,
Jialin Wang,
Guangyin Zhao,
Lianzhou Chen,
Yong Wan,
Qianxin Luo,
Wenwen Li,
Haoji Huang,
Wenying Li,
Wu Li,
Yutong Yang,
Daici Chen,
Qiao Su
Affiliations
Wuguo Li
Animal Experiment Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, PR China
Wei Chen
Department of Pathology, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, Guangdong, PR China
Jialin Wang
General Surgical Laboratory, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, PR China
Guangyin Zhao
Animal Experiment Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, PR China
Lianzhou Chen
General Surgical Laboratory, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, PR China
Yong Wan
Guangzhou Darui Biotechnology Co., Ltd., Guangzhou, Guangdong, PR China
Qianxin Luo
Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, PR China
Wenwen Li
Animal Experiment Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, PR China
Haoji Huang
Animal Experiment Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, PR China
Wenying Li
Animal Experiment Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, PR China
Wu Li
Animal Experiment Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, PR China
Yutong Yang
Animal Experiment Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, PR China
Daici Chen
Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, PR China; Corresponding author.
Qiao Su
Animal Experiment Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, PR China; Corresponding author.
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.
