MET inhibitors have shown promising efficacy for MET-dysregulated non-small cell lung cancer (NSCLC). However, quite a few patients cannot benefit from it due to the lack of powerful biomarkers. This study aims to explore the potential role of plasma proteomics-derived biomarkers for patients treated with MET inhibitors using mass spectrometry. We analyzed the plasma proteomics from patients with MET dysregulation (including MET amplification and MET overexpression) treated with MET inhibitors. Thirty-three MET-dysregulated NSCLC patients with longitudinal 89 plasma samples were included. We classified patients into the PD group and non-PD group based on clinical response. The baseline proteomic profiles of patients in the PD group were distinct from those in the non-PD group. Through protein screening, we found that a four-protein signature (MYH9, GNB1, ALOX12B, HSD17B4) could predict the efficacy of patients treated with MET inhibitors, with an area under the curve (AUC) of 0.93, better than conventional fluorescence in situ hybridization (FISH) or immunohistochemistry (IHC) tests. In addition, combining the four-protein signature with FISH or IHC test could also reach higher predictive performance. Further, the combined signature could predict progression-free survival for MET-dysregulated NSCLC (p < 0.001). We also validated the performance of the four-protein signature in another cohort of plasma using an enzyme-linked immunosorbent assay. In conclusion, the four plasma protein signature (MYH9, GNB1, ALOX12B, and HSD17B4 proteins) might play a substitutable or complementary role to conventional MET FISH or IHC tests. This exploration will help select patients who may benefit from MET inhibitors.

The underlying relationship between pyroptosis and tumorigenesis has garnered increasing attention recently. It has been demonstrated that the transcription factor MYB proto-oncogene-like 2 (MYBL2) is elevated in various solid tumors, thereby promoting cell proliferation. However, the role of MYBL2 gene in lung adenocarcinoma (LUAD), especially its potential connection with pyroptosis, is still unclear. Here, by combining ATAC seq and RNA seq methods, we initially identified MYBL2 gene as the main regulatory transcription factor (MR-TF) driving LUAD phenotype plasticity. An in-depth analysis of the sequencing results revealed that the expression of the MYBL2 gene was significantly higher in LUAD tissues than in normal tissues. Further experiments confirmed that MYBL2 promoted the proliferation of LUAD and attenuated tumor cell pyroptosis. Mechanistically, MYBL2 negatively regulated GSDME expression by binding to its promoter, thereby diminishing cisplatin-induced pyroptosis and ultimately leading to reduced chemosensitivity. Moreover, MYBL2 interacted with YAP1 to co-regulate GSDME transcription. The results of this research could be used to inform new strategies for screening effective populations and overcoming treatment resistance, making them potentially clinically valuable.