Resistance to targeted cancer therapies is a complex and critical challenge that researchers are actively tackling. In a groundbreaking collaboration, ATCC and the Broad Institute have developed a novel approach to studying this issue, focusing on non-small cell lung cancer (NSCLC) and the latest-generation epidermal growth factor receptor (EGFR) inhibitor, osimertinib. This innovative project aims to accelerate the discovery of new treatment strategies by creating engineered isogenic cancer models that replicate resistance mechanisms.
The development of drug resistance over time is a significant hurdle in oncology, and this collaboration directly addresses this challenge. By engineering resistance mechanisms into controlled laboratory models, researchers can efficiently study multiple escape pathways, a process that would typically take years using patient tumor samples.
Engineering Drug-Resistant Models
Led by experts from both institutions, the team identified key resistance mechanisms to osimertinib and selected three sensitive NSCLC cell lines as the foundation. ATCC then employed CRISPR-based methods to introduce specific resistance alterations into these authenticated cell lines. The resulting models capture a range of resistance mechanisms, including mutations in PIK3CA, KRAS, BRAF, and EGFR, as well as gene fusions involving CCDC6-RET and TPM3-NTRK1.
Additionally, scientists at the Broad Institute are generating resistant cell lines driven by gene amplification mechanisms. These engineered isogenic models provide a unique opportunity to study how tumors evolve under targeted therapy, as researchers can compare genetically matched cancer cells with and without specific resistance alterations.
Integrating Models and Data
The collaboration aims to integrate these models and associated data into the Cancer Dependency Map (DepMap), a global initiative to identify genetic vulnerabilities in cancer. This integration will enable researchers worldwide to access and analyze the data, facilitating the identification of new vulnerabilities and potential therapeutic combinations. The models will also contribute to the development of a Response and Resistance Map (ResMap), a framework for characterizing cancer responses to therapy and the evolution of resistance.
Impact and Future Directions
By establishing a scalable framework for studying tumor escape from targeted therapies, this collaboration has the potential to significantly impact cancer research and treatment. The resulting models and datasets will guide researchers in identifying new vulnerabilities and therapeutic strategies to overcome drug resistance. The combination of advanced cell engineering, functional genomics, and computational biology provides a powerful toolkit for studying drug resistance and precision oncology strategies.
The research findings will be presented at the American Association for Cancer Research® (AACR) Annual Meeting 2026, offering a platform to share and discuss these innovative approaches with the scientific community. This collaboration between ATCC and the Broad Institute showcases a promising path forward in the fight against cancer, offering hope for improved outcomes for patients.
