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Translating Gastric Cancer Genomics into Targeted Therapy: Mechanistic Insights from Animal Models and
Rong-Yaun Shyu1, Lu-Kai Wang2, Fu-Ming Tsai3
1Department of Internal Medicine, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City 231, Taiwan.
Abstract:
Gastric cancer remains a leading cause of cancer-related mortality worldwide and is marked by pronounced molecular heterogeneity. Advances in genomic profiling have identified key genetic alterations, including oncogenes (HER2, PIK3CA, and MYC), tumor suppressor genes (TP53, CDH1, and ARID1A), and regulators of genome stability and cell architecture (MLH1, RHOA, and CLDN18), which have driven the development of targeted therapeutic strategies. Although genetically engineered mouse models and xenograft systems have been indispensable for functional validation and preclinical drug testing, many approaches that showed promising efficacy in animal models-such as inhibition of EGFR, MET, FGFR2, and the PI3K pathway-failed to translate into overall survival benefits in clinical trials, highlighting major translational limitations. In contrast, HER2- and CLDN18.2-targeted therapies represent rare but notable clinical successes, underscoring the importance of true oncogenic dependency, precise biomarker-driven patient selection, and robust preclinical validation. In this review, we systematically categorize gastric cancer-associated genes according to their biological functions, summarize representative animal models, and critically examine key successes and failures in clinical translation, emphasizing the need for biologically faithful models and precision-driven translational strategies.
Insights
Gastric cancer research identifies key genes driving tumor growth and therapeutic targets. However, many targeted therapies fail in clinical trials, stressing the need for better preclinical models and patient selection for effective gastric cancer treatment.
Area of Science:
- Oncology
- Genetics
- Translational Medicine
Background:
- Gastric cancer is a major global health issue with significant molecular diversity.
- Genomic profiling reveals key oncogenes, tumor suppressors, and pathway regulators in gastric cancer.
- Existing preclinical models have limitations in predicting clinical efficacy of targeted therapies.
Purpose of the Study:
- To systematically review gastric cancer-associated genes and their biological functions.
- To summarize and evaluate animal models used in gastric cancer research.
- To critically analyze clinical translation successes and failures of targeted therapies.
Main Methods:
- Categorization of gastric cancer genes by biological function.
- Review of representative animal models for gastric cancer.
- Critical examination of clinical trial outcomes for targeted therapies.
Main Results:
- Identified key genes like HER2, PIK3CA, TP53, and CDH1 in gastric cancer.
- Highlighted translational challenges where therapies effective in models failed in patients.
- Noted success of HER2- and CLDN18.2-targeted therapies due to specific dependencies and patient selection.
Conclusions:
- Biologically faithful preclinical models are crucial for successful gastric cancer drug development.
- Precision-driven strategies, including biomarker-based patient selection, are essential for clinical translation.
- Understanding molecular heterogeneity is key to overcoming translational barriers in gastric cancer therapy.
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