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).
The identification of the location of the rs9387478 single nucleotide polymorphism in the genomic interval containing the DCBLD1 and ROS1 genes, together with the finding that the rs9387478 polymorphism correlates with EGFR mutation status, may have important implications for therapeutic approaches targeting EGFR or ROS1 in patients with lung cancer.
Collectively, these data suggest that each of these two ROS1-fusion genes acts as a driver for the pathogenesis of lung adenocarcinoma in vivo The TG mice developed in this study are expected to serve as valuable tools for exploring novel therapeutic agents against ROS1-fusion-positive 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.
Crizotinib was highly active at treating lung cancer in patients with a ROS1 rearrangement, suggesting that patients with lung adenocarcinomas should be tested for ROS1.
Activating alterations in several potential driver oncogenic genes have been identified, including EGFR, ROS1 and ALK and understanding of their molecular mechanisms underlying development, progression, and survival of lung cancer has led to the design of personalized treatments that have produced superior clinical outcomes in tumours harbouring these mutations.
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.
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.
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.
In addition to the lung cancer-related genes (TP53, EGFR, KRAS, PIK3CA, and ROS1), this study revealed "novel" genes not previously implicated in NSCLC.
We have used human lung cancer cell lines carrying a plasmid vector containing a (CA)(13) microsatellite sequence to study frameshift mutations mediated by ROS-generating chemicals paraquat and hydrogen peroxide.