Longitudinal Plasma Proteomics-Derived Biomarkers Predict Response to MET Inhibitors for MET-Dysregulated NSCLC

Simple Summary Targeted therapy has revolutionized the treatment of non-small cell lung cancer (NSCLC) and MET inhibition is a promising therapy for MET-dysregulated NSCLC. However, due to the lack of effective biomarkers, the clinical efficacy is unsatisfactory. This study aims to investigate the clinical utility of plasma proteomics-derived biomarkers for MET-dysregulated NSCLC (including MET amplification and MET overexpression). We analyzed 89 longitudinal plasma samples from MET-dysregulated advanced-stage NSCLC patients treated with MET inhibitors by the method of mass spectrometry. The results showed that the peripheral plasma proteomic characteristics were associated with the outcomes of patients treated with MET inhibitors. Through biomarker selection, we found a four plasma protein signature (MYH9, GNB1, ALOX12B, and HSD17B4 proteins) could predict the response and progression-free survival of patients treated with MET inhibitors with high accuracy. This study highlighted the clinical utilization of plasma biomarkers to scream patients to receive MET inhibitors. 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.

Automated summary

This study explores the clinical utility of plasma proteomics-derived biomarkers for MET-dysregulated NSCLC patients treated with MET inhibitors. Mass spectrometry analysis of longitudinal plasma samples revealed that the peripheral plasma proteomic characteristics were associated with treatment outcomes. A four-protein signature (MYH9, GNB1, ALOX12B, and HSD17B4) was identified as a high-accuracy predictor of response and progression-free survival in patients treated with MET inhibitors.