![]() ![]() Normal epithelial cells proliferate better under aerobic conditions, making it impractical to distinguish the effects of drugs on patient tumor and normal cells.īased on the conventional CR system, to guide the individualization of therapy, here we report a modified individual CR system (termed i-CR), characterized by selective expansion of tumor cells from CRC patients in vitro. ![]() A limitation of CR technology is its inability to distinguish between tumor and normal epithelial cells, as both proliferate well in the system. Thus, CR technology may guide the individualization of cancer treatment. The CR system can be used to expand normal and tumor cells from different tissues, including surgical specimens, biopsies, and PDX tissues. Recently, a novel primary cell culture technology, conditional reprogramming (CR), was reported by Liu and coworkers and allows expansion of primary epithelial cells in vitro with high efficiency. We established a primary tumor bank with various tissue types, including colorectal (CRC) and gastric cancers, but the cost and duration of the experiments and low throughput of the PDX models hindered achievement of treatment goals, especially for late-stage disease. Compared to conventional primary cell culture, PDX models and organoids can mimic patient genotypes, maintain intra-tumor heterogeneity, and evaluate the response to cancer therapies. Patient-derived xenograft (PDX) models and organoids are suitable surrogates for original tumors. Functional drug testing by traditional primary cell culture of patient tumor tissue is subject to the proliferation bias of different cell clones, which can lead to inaccurate results. To achieve individualized cancer therapy, novel preclinical models that more closely reflect the genomic complexity of cancers are needed. The novel i-CR system combined with PDX models will enable individualization of therapy and drug discovery, and strategies combining EGFR, MEK, and CDK4/6 inhibitors warrant clinical validation. These data were validated using paired PDX models, which showed marked inhibition of tumor growth. Using inhibitors targeting multiple signaling pathways identified by high-throughput i-CR drug screening, we discovered that inhibition of the EGFR and MEK or CDK4/6 pathways exerted a synergistic inhibitory effect against CRC, and we noted super-synergistic effects when EGFR, MEK, and CDK4/6 inhibitors were used simultaneously. The i-CR system selectively expanded tumor cells rather than normal epithelial cells and facilitated high-throughput drug screening when combined with high-content imaging and quantitative analysis of cell proliferation. Tumor samples from CRC patients were collected and PDX models were derived followed by high-throughput i-CR drug screening and validation of the effective targeted drug combinations. ![]() By modifying the ingredients of the culture medium used in a conventional CR system, a novel individualized CR system (termed i-CR) was established. We explored the optimum preclinical model by modifying the conventional conditional reprogramming (CR) system followed by screening effective targeted drug combinations against colorectal cancer (CRC). ![]() Preclinical models, including patient-derived xenograft (PDX) and organoid and primary cell culture, are essential for studies of cancer cell biology and facilitate translational research and individualization of therapy. ![]()
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