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<p>Effective cancer drug discovery requires experimental strategies that integrate mechanistic insight with clinical relevance. This review presents a conceptual framework in which CRISPR–Cas9 genome editing serves as the unifying technology linking disparate preclinical platforms. We examine experimental systems ranging from two-dimensional (2D) cultures to advanced three-dimensional (3D) models, including spheroids, patient-derived organoids, and microfluidic tumor-on-chip devices, that better recapitulate the tumor architecture and microenvironmental interactions. Core cellular assays for viability, migration, invasion, and apoptosis are evaluated for throughput, physiological relevance, and CRISPR compatibility. In vivo models, including xenografts, syngeneic systems, genetically engineered mouse models (GEMMs), and patient-derived xenografts (PDXs), are discussed for their roles in modeling tumor progression, immune interactions, and therapeutic response. Critically, we examine model-specific challenges affecting CRISPR delivery efficiency, editing heterogeneity, off-target effects, and context-dependent gene function and discuss emerging solutions, including base editing and single-cell screening. Despite persistent challenges in model fidelity and translational predictability, we argue that a strategically integrated, multimodel pipeline combining complementary assays, advanced models, and precise genome editing provides the most robust framework for improving target validation and accelerating the development of effective anticancer therapies.</p>

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Integrating Experimental Assays, Preclinical Models, and CRISPR-Based Functional Approaches for Cancer Drug Discovery

  • 期刊论文

  • 发表日期：

    2026年4月7日

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  • Cromwel Tepap Zemnou,
  • Ramelle Ngakam

摘要

Effective cancer drug discovery requires experimental strategies that integrate mechanistic insight with clinical relevance. This review presents a conceptual framework in which CRISPR–Cas9 genome editing serves as the unifying technology linking disparate preclinical platforms. We examine experimental systems ranging from two-dimensional (2D) cultures to advanced three-dimensional (3D) models, including spheroids, patient-derived organoids, and microfluidic tumor-on-chip devices, that better recapitulate the tumor architecture and microenvironmental interactions. Core cellular assays for viability, migration, invasion, and apoptosis are evaluated for throughput, physiological relevance, and CRISPR compatibility. In vivo models, including xenografts, syngeneic systems, genetically engineered mouse models (GEMMs), and patient-derived xenografts (PDXs), are discussed for their roles in modeling tumor progression, immune interactions, and therapeutic response. Critically, we examine model-specific challenges affecting CRISPR delivery efficiency, editing heterogeneity, off-target effects, and context-dependent gene function and discuss emerging solutions, including base editing and single-cell screening. Despite persistent challenges in model fidelity and translational predictability, we argue that a strategically integrated, multimodel pipeline combining complementary assays, advanced models, and precise genome editing provides the most robust framework for improving target validation and accelerating the development of effective anticancer therapies.