New targets in thymic epithelial tumours may aid in identifying treatment options

Thymomas and thymic carcinomas (constituting the thymic epithelial tumours [TETs]) are rare epithelial tumours. 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) of TETs has 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 tumour pathogenesis and identification of novel drug targets.

Guha et al. hypothesised that a global proteomics approach may elucidate altered signalling pathways in TETs that can be potentially targeted. To investigate this, 3-state SILAC quantitative mass spectrometry was used to characterise the global proteome and phosphoproteome of TETs, aiming to identify potential actionable drivers in thymomas and thymic carcinomas. Two thymoma (IU-TAB1 and T1682) and three thymic carcinoma cell lines (MP57, T1889, and Ty82) were assessed. Additionally, 10-plex TMT quantitative proteomics was used to quantify the global proteomes and phosphoproteomes of 54 TET tumours. All tumour tissues were pooled together to make the reference channel and labelled with TMT10-131.

A total of 4,756 proteins and 5,690 phosphorylation sites from TET cell lines were identified. Hierarchical clustering of SILAC ratios of quantitation demonstrated that T1682 and MP57 cell lines were more similar to each other than T1889 and Ty82. Several metabolic enzymes (LDHB, GSTP1, and AKR1B1) had higher expression in thymic carcinoma lines, while mitochondrial glutamate carrier SLC25A22 had greater abundance in thymoma lines. Pathway analysis revealed that the significantly changed proteins in TET were associated with the remodelling of epithelial adherens junction, mitochondria dysfunction, and oxidative phosphorylation. RAS signalling pathway was enriched among the significantly changed phosphorylation sites in the thymic MP57 and the B1 thymoma T1682 cells.

The proteome and phosphoproteome of 54 TET tumour samples from 28 patients (23 thymoma and 5 thymic carcinoma) undergoing surgery or biopsy using TMT mass spectrometry was also analysed. In total, 8,320 proteins and 17,716 phosphorylation sites were identified. Hierarchical clustering of the TMT ratios to the pool for both proteins and phosphorylation sites demonstrated that thymomas and thymic carcinomas clustered separately. Different locations of tumours from the same patient were grouped together. Only a few tumour locations from the thymoma patients clustered in the thymic carcinoma group. The results made clear that glutathione S-transferase pi 1 (GSTP1) protein is highly expressed in thymic carcinomas. Also, several kinases, including PDGFRB, RIOK1, TNIK, and MAP4K4 have higher expression in thymic tumours compared to thymomas.

The presented results may offer new treatment approaches, as it was shown that 3 different GSTP1 inhibitors (LAS17, ezatiostat, and resveratrol) are effective in inhibiting the growth of TETs with GSTP1 expression [1].

1. Guha U, et al. MA20.01. WCLC 2019.

Posted on 8 November 20195 March 2021