Clinicopathological characteristics of Non-Small Cell Lung Cancer (NSCLC) patients with c-MET exon 14 skipping mutation, MET overexpression and amplification.

PURPOSE: MET exon 14 skipping is one of the rare mutations in non-small cell lung cancer (NSCLC), involving its pathogenesis and progression. The performances of several MET inhibitors in clinical trials have been validated based on NGS, immunohistochemistry (IHC), and gene copy number assessments. Thus, a detailed understanding of the relationship between these markers and prognosis is required. METHODS: This study has recruited patients (n = 17) with MET exon 14 skipping mutation and initially screened genes (n = 10) by polymerase chain reaction (PCR) from 257 specimens of NSCLC, including small biopsies and surgical resection. Further, the IHC analysis detected MET overexpression and recorded the score using the MetMAb trial (rial ( recruited patients (n = 17) with MET exstainings). Finally, the fluorescence in situ hybridization (FISH) resulted in the MET amplification with a MET copy number initially screened genes (n = 10) by p. RESULTS: PCR results indicated strong MET staining ( 3+) in more than 50% of tumor cells. Among the recruited 17 cases of MET exon 14 skipping, 9 cases presented MET amplification, and 10 cases with MET overexpression. These attributes were not correlated to the clinicopathological characteristics and overall survival. In addition, 4 cases showed gene amplification, and 3 cases presented polyploidy condition. The correlation analysis showed a significant relationship between MET amplification and MET overexpression (Pearson's r2 = 0.4657, P < 0.005). CONCLUSION: Together, these findings indicated a significant correlation between MET overexpression and MET amplification in NSCLC patients but no correlation to prognosis.

Design, synthesis, and evaluation of chalcone analogues incorporate α,ß-Unsaturated ketone functionality as anti-lung cancer agents via evoking ROS to induce pyroptosis.

Chalcone, a natural structure, demonstrates many pharmacological activities including anticancer, and one promising mechanism is to modulate the generation of ROS. It has been known that pyroptosis is associated with anticancer effects, whereas there is fewer researches about ROS-mediated pyroptosis triggered by chemotherapy drugs. Moreover, incorporation of a α,ß-unsaturated ketone unit into chalcone may be an effective strategy for development of chemotherapy drugs. Hence, a number of chalcone analogues bearing a α,ß-unsaturated ketone were synthesized from chalcone analogues 1 with modest anticancer activities as the lead compound. Structure-activity relationship (SAR) studies confirmed the function of α,ß-unsaturated ketone to improve anticancer activity. Notably, compound 8, bearing a α,ß-unsaturated ketone, is the most potent inhibitor of cancer, with IC50 values on NCI-H460, A549 and H1975 cells of 2.3 ±â€¯0.3, 3.2 ±â€¯0.0 and 5.7 ±â€¯1.4 µM, respectively. Besides, 8 showed antiproliferative ability against NCI-H460 cells in a time- and concentration-dependent manner through modulating ROS to induce caspase-3-mediated pyroptosis, and displayed a better safety profile in vivo. Overall, these results demonstrated that compound 8 is a candidate agent and a potential lead compound for development of chemotherapy drugs, and can be used as a probe to further examine the mechanism of ROS-dependent pyroptosis.