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.
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