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Recent Advances in Targeting ROS1 in Lung Cancer
1Massachusetts General Hospital Cancer Center, Boston, Massachusetts.
Abstract:
ROS1 is a validated therapeutic target in NSCLC. In a phase I study, the multitargeted MET proto-oncogene, receptor tyrosine kinase/anaplastic lymphoma kinase/ROS1 inhibitor crizotinib demonstrated remarkable efficacy in ROS1-rearranged NSCLCs and consequently gained approval by the United States Food and Drug Administration and by the European Medicines Agency in 2016. However, similar to other oncogene-driven lung cancers, ROS1-rearranged lung cancers treated with crizotinib eventually acquire resistance, leading to disease relapse. Novel ROS1 inhibitors and therapeutic strategies are therefore needed. Insights into the mechanisms of resistance to ROS1-directed tyrosine kinase inhibitors are now beginning to emerge and are helping to guide the development of new ROS1 inhibitors. This review discusses the biology and diagnosis of ROS1-rearranged NSCLC, and current and emerging treatment options for this disease. Future challenges in the field are highlighted.
Insights
Crizotinib effectively treats ROS1-rearranged non-small cell lung cancer (NSCLC), but resistance develops. New ROS1 inhibitors are crucial for overcoming treatment resistance in NSCLC patients.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- ROS1 rearrangements define a subset of non-small cell lung cancer (NSCLC) with a validated therapeutic target.
- Crizotinib, a multitargeted tyrosine kinase inhibitor, gained regulatory approval for ROS1-rearranged NSCLC.
- Acquired resistance to crizotinib limits long-term efficacy, necessitating alternative therapeutic strategies.
Purpose of the Study:
- To review the biology and diagnosis of ROS1-rearranged NSCLC.
- To discuss current and emerging treatment options for ROS1-rearranged NSCLC.
- To highlight future challenges in targeting ROS1 in NSCLC.
Main Methods:
- Literature review of studies on ROS1-rearranged NSCLC.
- Analysis of clinical trial data for crizotinib and other ROS1 inhibitors.
- Discussion of emerging resistance mechanisms and novel therapeutic approaches.
Main Results:
- Crizotinib shows significant efficacy in ROS1-rearranged NSCLC but is associated with eventual acquired resistance.
- Emerging insights into resistance mechanisms are guiding the development of next-generation ROS1 inhibitors.
- Several novel ROS1 inhibitors are under investigation for overcoming resistance and improving patient outcomes.
Conclusions:
- ROS1-rearranged NSCLC is a distinct molecular subtype requiring targeted therapy.
- Understanding and overcoming resistance to tyrosine kinase inhibitors is critical for durable responses.
- Continued research into novel inhibitors and treatment strategies is essential for advancing care in ROS1-rearranged NSCLC.
