Although full-length ROS1 is expressed in some ROS1-non-rearranged cases, we showed that establishment of an optimal set of interpretative criteria makes ROS1 immunohistochemistry a valuable method to rapidly and accurately screen lung cancer patients for appropriate molecular therapy.
Although high response rates and disease control have been observed in lung cancer patients bearing rearranged ROS1 tumors (ROS1+) treated with the kinase inhibitor crizotinib, many of these patients eventually relapse.To identify mechanisms of resistance to ROS1 inhibitors we generated resistant cells from HCC78 lung cancer cells bearing the SLC34A2-ROS1 rearrangement.
We analyzed cases with lung adenocarcinomas for representative genomic aberrations, evaluated the response to the multitargeted MET/ALK/ROS1 crizotinib TKI in cases with MET aberrations and profiled lung cancer cell lines with the aforementioned genomic changes.
Key eligibility criteria included patients who were 18 years of age or older with advanced/metastatic lung cancer and centrally confirmed ROS1-rearranged lung cancer (fluorescence-in situ hybridization).
These data confirmed that CG caused apoptosis through the activation of extrinsic and intrinsic pathways, cell cycle arrest, and ROS generation in A549 and NCI-H1299 lung cancer cells.
The College of American Pathologists/International Association for the Study of Lung Cancer/Association for Molecular Pathology testing guidelines support the use of ROS1 immunohistochemistry (IHC) as a screening test, followed by confirmation with fluorescence in situ hybridization (FISH) or a molecular test in all positive results.
In addition to the lung cancer-related genes (TP53, EGFR, KRAS, PIK3CA, and ROS1), this study revealed "novel" genes not previously implicated in NSCLC.
Conversely, restricting ROS generation and/or targeting YY1 in lung cancer cells effectively inhibits the EGFR-MnSOD signaling pathway and cell invasiveness induced by MCT-1.
Epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), and ROS proto-oncogene 1 (ROS1) are 'must-test' biomarkers in the molecular diagnostics of advanced-stage lung cancer patients.
In conclusion, the present study indicates that the new synthetic derivative MA-1 triggers mitochondrial apoptosis through ROS generation and regulation of MAPKs and may be a potent therapeutic agent against human lung cancer.
The molecular target drugs for lung cancer with anaplastic lymphoma kinase (ALK) gene translocation (the fusion gene, EML4-ALK) was approved, and those targeting lung cancers addicted ROS1, RET, and HER2 have been under development.
Interestingly, the overall survival of the 13 ROS1-positive patients with lung cancer from initiation of pemetrexed-based chemotherapy was significantly prolonged when compared with that of 169 pemetrexed-treated patients with EGFR/anaplastic lymphoma kinase/ROS1-negative adenocarcinoma (p = 0.01).
Crizotinib was the first tyrosine kinase inhibitor to demonstrate activity in ROS1-rearranged lung cancer, and remains the recommended first-line therapy for patients with advanced ROS1-rearranged non-small cell lung cancer.