Overview of Preclinical Drug‐Resistant Tumor Models and Their Application in Drug Discovery

Abstract Cancer drug resistance, whether intrinsic or acquired, underlies most relapses and treatment failures. Reliable preclinical models are crucial to define resistance mechanisms and test counterstrategies. This overview article concisely compares three model classes: (1) clinical, patient‑derived xenografts that retain tumor heterogeneity and can mirror patient resistance; (2) induced‑resistance models produced by prolonged drug selection in vivo or in vitro that recapitulate tumor evolution under therapy; and (3) engineered isogenic cell lines that isolate specific resistance drivers. We summarize some key resistance mechanisms revealed and potential therapeutic approaches informed by these models, including rational combinations, mutation‑targeted inhibitors/degraders, efflux/epigenetic modulators, and immune‐related combinations. Each model has trade‑offs, but integrating them accelerates mechanistic insight and translational drug development. This overview guides selection of preclinical models and design of strategies to overcome cancer drug resistance. © 2025 Wiley Periodicals LLC.