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Khoa Dang Nguyen



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    MA20 - Thymic Tumors: From Molecular to Clinical Results and New Challenges in Other Rare Thoracic Tumors (ID 149)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Thymoma/Other Thoracic Malignancies
    • Presentations: 1
    • Now Available
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      MA20.01 - Global Quantitative Mass Spectrometry Reveals Potential Novel Actionable Targets in Thymic Epithelial Tumors (TET)   (Now Available) (ID 2294)

      11:30 - 13:00  |  Author(s): Khoa Dang Nguyen

      • Abstract
      • Presentation
      • Slides

      Background

      Thymomas (T) and thymic carcinomas (TC), that constitute the thymic epithelial tumors (TETs) are rare epithelial tumors. There are limited treatment options for patients with advanced TETs. The complexity and rarity of the disease hampers the development of effective therapeutics. Next-generation sequencing (NGS) analyses of TETs by the TCGA have confirmed the very low mutational burden and few actionable targets for therapy. Thus, novel strategies are needed for better elucidating the molecular pathways involved in tumor pathogenesis and identification of novel drug targets. Here, we have used quantitative mass spectrometry (MS) to characterize the global proteome and phosphoproteome of TETs with aim of identifying potential actionable drivers in thymomas and thymic carcinomas.

      Method

      Three-state SILAC quantitative mass spectrometry was used to quantify the global proteomes and phosphoproteomes of two thymoma (IU-TAB1 and T1682) and three thymic carcinoma cell lines (MP57, T1889 and Ty82). 10-plex TMT quantitative proteomics was used to quantify the global proteomes and phosphoproteomes of 54 TET tumors. All tumor tissues were pooled together to make the reference channel and labeled with TMT10-131. Basic RPLC followed by TiO2 enrichment and tandem MS were performed in a Q ExactiveTM HF mass spectrometer. MS data was processed using MaxQuant and Perseus. Protein quantification, normalization and statistical testing for the TMT experiments was done using free R package MSstatsTMT.

      Result

      We identified 4756 proteins and 5690 phosphosites from TET cell lines. Hierarchical clustering of SILAC ratios of quantitation demonstrated that T1682 and MP57 were more similar to each other than T1889 and Ty82. Several metabolic enzymes (LDHB, GSTP1, and AKR1B1) had higher expression in TC lines, while mitochondrial glutamate carrier SLC25A22 had greater abundance in thymoma lines. Ingenuity pathway analysis revealed that the top enriched canonical pathways associated with the significantly changed proteins in TET included remodeling of epithelial adherens junction, mitochondria dysfunction, and oxidative phosphorylation. RAS signaling pathway was enriched among the significantly changed phosphosites in the thymic MP57 and the B1 thymoma T1682 cells. We further analyzed the proteome and phosphoproteome of 54 TET tumor samples from 28 patients (23 thymoma and 5 thymic carcinoma) undergoing surgery or biopsy using TMT mass spectrometry. In total, 8320 proteins and 17716 phosphosites were identified. Hierarchical clustering of the TMT ratios to the pool for both proteins and phosphosites demonstrated that thymomas and thymic carcinomas clustered separately. Different locations of tumors from the same patient were grouped together. Only a few sites from the thymoma patients clustered in the thymic carcinoma group. GTF2I had higher abundance in thymomas compared to the TCs. MCM complex proteins and solute carrier family proteins had lower abundance and several collagens had higher abundance in TC patients. Several kinases, including PDGFRB, RIOK1, TNIK, and MAP4K4, and the metabolic enzyme glutathione S-transferase (GSTP1) had higher expression in TC patients. Further bioinformatics analysis and validation experiments are currently underway. Sensitivity data to inhibitors of metabolic enzymes and target kinases will be presented.

      Conclusion

      Global quantitative proteome and phosphoproteome analyses revealed potential novel kinases and metabolic enzymes for targeted therapy of TETs.

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