Abstract
The ROS-1 gene plays a major role in the oncogenesis of numerous tumors. ROS-1 rearrangement is found in 0.9–2.6% of non-small-cell lung cancers (NSCLCs), mostly lung adenocarcinomas, with a significantly higher rate of women, non-smokers, and a tendency to a younger age. It has been demonstrated that ROS-1 is a true oncogenic driver, and tyrosine kinase inhibitors (TKIs) targeting ROS-1 can block tumor growth and provide clinical benefit for the patient. Since 2016, crizotinib has been the first-line reference therapy, with two-thirds of the patients’ tumors responding and progression-free survival lasting ~20 months. More recently developed are ROS-1-targeting TKIs that are active against resistance mechanisms appearing under crizotinib and have better brain penetration. This review summarizes current knowledge on ROS-1 rearrangement in NSCLCs, including the mechanisms responsible for ROS-1 oncogenicity, epidemiology of ROS-1-positive tumors, methods for detecting rearrangement, phenotypic, histological, and molecular characteristics, and their therapeutic management. Much of this work is devoted to resistance mechanisms and the development of promising new molecules.
Highlights
Lung cancer represents the leading cause of cancer deaths worldwide, with more than1.8 million deaths in 2020 [1]; 85% are non-small-cell lung cancers (NSCLCs) and 25% of them harbor oncogenic alterations that can be targeted by therapy
The results of several studies showed that the presence of CD74–ROS-1 rearrangement was associated with longer progression-free survival (PFS) and overall survival (OS) than non-CD74–ROS-1 rearrangement [36]
Two tyrosine kinase inhibitors (TKIs) have been validated as first-line therapy for ROS-1-positive NSCLCs: crizotinib, approved in 2016 by the Food Drug Administration (FDA) and the European Medications Agency (EMA), and entrectinib approved by the FDA in 2019 and EMA in 2020 [3,4]
Summary
Lung cancer represents the leading cause of cancer deaths worldwide, with more than. 1.8 million deaths in 2020 [1]; 85% are non-small-cell lung cancers (NSCLCs) and 25% of them harbor oncogenic alterations that can be targeted by therapy. 1.8 million deaths in 2020 [1]; 85% are non-small-cell lung cancers (NSCLCs) and 25% of them harbor oncogenic alterations that can be targeted by therapy. That is the case for patients whose tumors are positive for proto-oncogene tyrosine-protein kinase-1 (ROS-1; c-Ros oncogene-1)-gene fusion. Despite initial responses, ROS-1-positive NSCLCs develop resistances to crizotinib, allowing tumor progression, notably brain metastases. More recently devised new molecules are active against crizotinib resistances and have good brain penetration. This present review is an update of those previous reviews [5,6] and describes our current knowledge of ROS-1 rearrangement in NSCLCs, including their diagnostic modalities, epidemiology, and characteristics, and the development of diverse molecules targeting.
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