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Updated: Aug 2, 2025
Author Spotlight: Establishing a Murine Non-Small Cell Lung Cancer Model for Developing Nanoformulations of Anticancer Drugs
Published on: May 10, 2024
Pre-clinical modelling of ROS1+ non-small cell lung cancer
Marc Terrones1, Ken Op de Beeck1, Guy Van Camp1
1Center of Medical Genetics, University of Antwerp and Antwerp University Hospital, Prins Boudewijnlaan 43/6, 2650 Edegem, Belgium; Center for Oncological Research, University of Antwerp and Antwerp University Hospital, Universiteitsplein 1, 2610 Wilrijk, Belgium.
Abstract:
Non-small cell lung cancer (NSCLC) is a heterogeneous group of diseases which accounts for 80% of newly diagnosed lung cancers. In the previous decade, a new molecular subset of NSCLC patients (around 2%) harboring rearrangements of the c-ros oncogene 1 was defined. ROS1+ NSCLC is typically diagnosed in young, nonsmoker individuals presenting an adenocarcinoma histology. Patients can benefit from tyrosine kinase inhibitors (TKIs) such as crizotinib and entrectinib, compounds initially approved to treat ALK-, MET- or NTRK- rearranged malignancies respectively. Given the low prevalence of ROS1-rearranged tumors, the use of TKIs was authorized based on pre-clinical evidence using limited experimental models, followed by basket clinical trials. After initiating targeted therapy, disease relapse is reported in approximately 50% of cases as a result of the appearance of resistance mechanisms. The restricted availability of TKIs active against resistance events critically reduces the overall survival. In this review we discuss the pre-clinical ROS1+ NSCLC models developed up to date, highlighting their strengths and limitations with respect to the unmet clinical needs. By combining gene-editing tools and novel cell culture approaches, newly developed pre-clinical models will enhance the development of next-generation tyrosine kinase inhibitors that overcome resistant tumor cell subpopulations.
Insights
New preclinical models are crucial for developing effective treatments for ROS1-positive non-small cell lung cancer (NSCLC). These models aim to overcome resistance mechanisms and improve patient survival in this rare cancer subset.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Non-small cell lung cancer (NSCLC) is a major cause of cancer death, with ROS1 rearrangements found in about 2% of cases.
- ROS1-positive NSCLC typically affects younger, non-smoking individuals with adenocarcinoma.
- Current tyrosine kinase inhibitors (TKIs) offer benefits but face challenges due to resistance and limited availability.
Purpose of the Study:
- To review existing preclinical models for ROS1-positive NSCLC.
- To highlight the strengths and limitations of these models in addressing clinical needs.
- To emphasize the importance of novel models for developing next-generation TKIs.
Main Methods:
- Review of existing literature on preclinical models for ROS1-positive NSCLC.
- Analysis of model development, including gene-editing tools and cell culture techniques.
- Evaluation of model utility in studying TKI resistance mechanisms.
Main Results:
- Limited preclinical models exist for ROS1-positive NSCLC, often based on initial TKI approvals.
- Disease relapse occurs in about 50% of patients due to resistance mechanisms.
- Existing models have limitations in fully recapitulating clinical resistance scenarios.
Conclusions:
- Advanced preclinical models are essential for understanding and overcoming TKI resistance in ROS1-positive NSCLC.
- Combining gene-editing and novel cell culture approaches can create more robust models.
- These improved models will accelerate the development of next-generation TKIs for improved patient outcomes.
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