Recent Advances in Cancer Drug Discovery Through the Use of Phenotypic Reporter Systems, Connectivity Mapping, and Pooled CRISPR Screening
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Updated: Oct 3, 2026
A Multiplexed Luciferase-based Screening Platform for Interrogating Cancer-associated Signal Transduction in Cultured Cells
Published on: July 3, 2013
Natasha Salame1, Katharine Fooks2,3, Nehme El-Hachem4
1Department of Biomedical Sciences, Université de Montréal, Montreal, QC, Canada.
Abstract:
Multi-omic approaches offer an unprecedented overview of the development, plasticity, and resistance of cancer. However, the translation from anti-cancer compounds identified in vitro to clinically active drugs have a notoriously low success rate. Here, we review how technical advances in cell culture, robotics, computational biology, and development of reporter systems have transformed drug discovery, enabling screening approaches tailored to clinically relevant functional readouts (e.g., bypassing drug resistance). Illustrating with selected examples of "success stories," we describe the process of phenotype-based high-throughput drug screening to target malignant cells or the immune system. Second, we describe computational approaches that link transcriptomic profiling of cancers with existing pharmaceutical compounds to accelerate drug repurposing. Finally, we review how CRISPR-based screening can be applied for the discovery of mechanisms of drug resistance and sensitization. Overall, we explore how the complementary strengths of each of these approaches allow them to transform the paradigm of pre-clinical drug development.
Insights
Advancing cancer drug discovery requires integrating multi-omic data with innovative screening methods. This review highlights how new technologies improve the translation of anti-cancer compounds from lab to clinic, overcoming resistance.
Area of Science:
- Oncology
- Pharmacology
- Biotechnology
Background:
- Multi-omic approaches provide comprehensive insights into cancer biology, including development, plasticity, and resistance.
- The translation of anti-cancer compounds from in vitro identification to clinical application faces significant challenges, with a historically low success rate.
Purpose of the Study:
- To review how technical advancements in various fields are transforming cancer drug discovery.
- To explore how these advancements enable screening approaches with clinically relevant functional readouts, such as overcoming drug resistance.
- To discuss the integration of phenotype-based screening, computational drug repurposing, and CRISPR-based screening for pre-clinical drug development.
Main Methods:
- Review of technical advances in cell culture, robotics, computational biology, and reporter systems.
- Description of phenotype-based high-throughput drug screening targeting malignant cells or the immune system.
- Explanation of computational methods linking cancer transcriptomic profiles with pharmaceutical compounds for drug repurposing.
- Overview of CRISPR-based screening for identifying mechanisms of drug resistance and sensitization.
Main Results:
- Technical innovations have enabled the development of drug screening approaches tailored to clinically relevant functional readouts, including bypassing drug resistance.
- Phenotype-based screening, computational drug repurposing, and CRISPR-based screening represent powerful tools for identifying and validating anti-cancer compounds.
- Selected examples demonstrate successful applications of these methodologies in advancing pre-clinical drug development.
Conclusions:
- The synergistic application of advanced cell culture, robotics, computational biology, and reporter systems is revolutionizing cancer drug discovery.
- These integrated approaches facilitate the identification of effective anti-cancer therapies by addressing challenges like drug resistance and enabling drug repurposing.
- The complementary strengths of these diverse methodologies are transforming the paradigm of pre-clinical drug development, paving the way for more successful clinical translation.
