Systematic Identification of Molecular Signatures Dictating Therapeutic Effects of Clinically First‐Line Chemotherapy Regimens for Human Gastric Cancer Patients Based on Organoid Model

Chemotherapy is the mainstay in the treatment of advanced gastric cancer (GC); yet, GC showed diverse responses to first-line chemotherapy regimens and the underlying molecular basis is still not clear. Here, we established a system that combined organoid-based chemotherapy regimen screening and transcriptome-based evaluation to identify underlying molecular signatures of different responses to chemotherapy. We generated 19 GC patient-derived organoids (PDOs) from surgically resected specimens with corresponding histological characteristics of parent tumors and tested all of the five most commonly used first-line chemotherapy regimens. Based on the treatment responses, PDOs were classified into double-sensitive, single-sensitive, and not-sensitive groups. PDOs that responded well to chemotherapy presented high expression levels of the P53 pathway genes and low expression levels of cell proliferative activity genes. Furthermore, the chemotherapy-based tumor classification of GC was established. The GC tumor classification was verified by multi-omics features from the TCGA dataset and public drug response datasets. In conclusion, this study systematically evaluated clinical chemotherapy regimens for GC and identified chemotherapy response-associated molecular signatures based on human GC organoids, which are beneficial to the precise treatments of GC.