Posts tagged proteomics

Abstract 1865: Phosphoproteomic analyses identify EGFR as a critical cooperative kinase for ALK

In order to interrogate the contribution of EGFR to downstream signaling under ALK inhibition, we conducted phosphoproteomics for two ALK-driven cell lines, DFCI032 and H3122, using the ALK inhibitor crizotinib or in combination with the EGFR inhibitor gefitinib. Kinase-Substrate Enrichment Analysis (KSEA) and Phosphoproteomics Dissection Using Networks (PHOTON) analysis were used to identify whether a signaling node was functionally regulated based on substrate phosphorylation or on protein-protein interaction partner phosphorylation, respectively. Strikingly, both methods showed that EGFR was functionally downregulated by ALK inhibition. ALK was also considered functionally more downregulated under EGFR/ALK dual inhibition compared to ALK inhibition alone by KSEA analysis. These data suggest ALK and EGFR engage in overlapping signaling pathways. Collectively, EGFR and ALK dual inhibition can significantly delay or prevent the emergence of ALK TKI resistance by suppressing critical overlapping signaling pathways and promotes signaling reprogramming in cancer cells. READ ARTICLE

AACR abstract DOI: 10.1158/1538-7445.AM2020-1865

Authors: Nan Chen, Anh T. Le, Andrea E. Doak, Guolin Zhang, Bin Fang, Eric B. Haura and Robert C. Doebele

Pre-ClinicalKirk SmithAugust 1, 2020ALK, EGFR, proteomics

Proteogenomic Characterization Reveals Therapeutic Vulnerabilities in Lung Adenocarcinoma

Summary: To explore the biology of lung adenocarcinoma (LUAD) and identify new therapeutic opportunities, we performed comprehensive proteogenomic characterization of 110 tumors and 101 matched normal adjacent tissues (NATs) incorporating genomics, epigenomics, deep-scale proteomics, phosphoproteomics, and acetylproteomics. Multi-omics clustering revealed four subgroups defined by key driver mutations, country, and gender. Proteomic and phosphoproteomic data illuminated biology downstream of copy number aberrations, somatic mutations, and fusions and identified therapeutic vulnerabilities associated with driver events involving KRAS, EGFR, and ALK. Immune subtyping revealed a complex landscape, reinforced the association of STK11 with immune-cold behavior, and underscored a potential immunosuppressive role of neutrophil degranulation. Smoking-associated LUADs showed correlation with other environmental exposure signatures and a field effect in NATs. Matched NATs allowed identification ..... READ ARTICLE

Cell DOI:10.1016/j.cell.2020.06.013

Authors: Michael A. Gillette, Shankha Satpathy, Song, Cao,.. AND MANY MORE

Review PaperKirk SmithJuly 9, 2020Lung cancer, adenocarcinoma, proteogenomics, proteomics, genomics, mass spectrometry, protein, phosphorylation, acetylation, CPTAC