Sialyltransferase ST3GAL4 confers osimertinib resistance and offers strategies to overcome resistance in non-small cell lung cancer

Han, Rui; Lin, Caiyu; Lu, Conghua; Wang, Yubo; Kang, Jun; Hu, Chen; Dou, Yuanyao; Wu, Di; He, TingTing; Tang, Huan; Zheng, Jie; Li, Li; He, Yong

doi:10.1016/j.canlet.2024.216762

Cited by 3 publications

(2 citation statements)

References 46 publications

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“…We also identified 2 putatively druggable glycoproteins (laminin alpha5 (LAMA5) and laminin gamma 1 (LAMC1)) with known but as yet non-FDA approved molecules. It was worth noting that most core-fucosylated sites were localized in the extracellular domains of these glycoproteins, which played an important role in mediating the functions of proteins. , For example, the core-fucosylated site N196 on EGFR and N785 on MET were localized in the extracellular domains that were essential for the activation of EGFR and MET, respectively. , Furthermore, the core-fucosylated site N196 on EGFR was near the monoclonal antibody (such as cetuximab) binding sites. , In addition, 73 upregulated core-fucosylated sites were observed on 64 secreted glycoproteins, among which 27 glycoproteins were annotated as plasma proteins (Figure S16). These upregulated core-fucosylated sites might have the potential to serve as biomarkers for early detection of LUAD, e.g., VWF-N2585, TIMP1-N53, SERPINA1-N271, CP-N358, and CLU-N86 (Figure D).…”

Section: Resultsmentioning

confidence: 99%

“… 47 , 48 For example, the core-fucosylated site N196 on EGFR and N785 on MET were localized in the extracellular domains that were essential for the activation of EGFR and MET, respectively. 48 , 49 Furthermore, the core-fucosylated site N196 on EGFR was near the monoclonal antibody (such as cetuximab) binding sites. 50 , 51 In addition, 73 upregulated core-fucosylated sites were observed on 64 secreted glycoproteins, among which 27 glycoproteins were annotated as plasma proteins ( Figure S16 ).…”

Section: Resultsmentioning

confidence: 99%

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A “One-Step” Strategy for the Global Characterization of Core-Fucosylated Glycoproteome

Wang,

Yuan,

Liang

et al. 2024

JACS Au

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Core fucosylation, a special type of N-linked glycosylation, is important in tumor proliferation, invasion, metastatic potential, and therapy resistance. However, the core-fucosylated glycoproteome has not been extensively profiled due to the low abundance and poor ionization efficiency of glycosylated peptides. Here, a "one-step" strategy has been described for protein corefucosylation characterization in biological samples. Core-fucosylated peptides can be selectively labeled with a glycosylated probe, which is linked with a temperature-sensitive poly(N-isopropylacrylamide) (PNIPAM) polymer, by mutant endoglycosidase (EndoF3-D165A). The labeled probe can be further removed by wild-type endoglycosidase (EndoF3) in a traceless manner for mass spectrometry (MS) analysis. The feasibility and effectiveness of the "one-step" strategy are evaluated in bovine serum albumin (BSA) spiked with standard core-fucosylated peptides, H1299, and Jurkat cell lines. The "one-step" strategy is then employed to characterize core-fucosylated sites in human lung adenocarcinoma, resulting in the identification of 2494 core-fucosylated sites distributed on 1176 glycoproteins. Further data analysis reveals that 196 core-fucosylated sites are significantly upregulated in tumors, which may serve as potential drug development targets or diagnostic biomarkers. Together, this "one-step" strategy has great potential for use in global and in-depth analysis of the core-fucosylated glycoproteome to promote its mechanism research.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

A “One-Step” Strategy for the Global Characterization of Core-Fucosylated Glycoproteome

Wang,

Yuan,

Liang

et al. 2024

JACS Au

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Sialylation in the gut: From mucosal protection to disease pathogenesis

Ma,

Li,

Wang

et al. 2024

Carbohydrate Polymers

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Xanthohumol overcomes osimertinib resistance via governing ubiquitination-modulated Ets-1 turnover

Ma,

Wang,

Liao

et al. 2024

Cell Death Discov.

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Non-small cell lung cancer (NSCLC) is a prevalent and fatal malignancy with a significant global impact. Recent advancements have introduced targeted therapies like tyrosine kinase inhibitors (TKIs) such as osimertinib, which have improved patient outcomes, particularly in those with EGFR mutations. Despite these advancements, acquired resistance to TKIs remains a significant challenge. Hence, one of the current research priorities is understanding the resistance mechanisms and identifying new therapeutic targets to improve therapeutic efficacy. Herein, we identified high expression of c-Met in osimertinib-resistant NSCLC cells, and depletion of c-Met significantly inhibited the proliferation of osimertinib-resistant cells and prolonged survival in mice, suggesting c-Met as an attractive therapeutic target. To identify effective anti-tumor agents targeting c-Met, we screened a compound library containing 641 natural products and found that only xanthohumol exhibited potent inhibitory effects against osimertinib-resistant NSCLC cells. Moreover, combination treatment with xanthohumol and osimertinib sensitized osimertinib-resistant NSCLC cells to osimertinib both in vitro and in vivo. Mechanistically, xanthohumol disrupted the interaction between USP9X and Ets-1, and inhibited the phosphorylation of Ets-1 at Thr38, promoting its degradation, thereby targeting the Ets-1/c-Met signaling axis and inducing intrinsic apoptosis in osimertinib-resistant NSCLC cells. Overall, the research highlights the critical role of targeting c-Met to address osimertinib resistance in NSCLC. By demonstrating the efficacy of xanthohumol in overcoming resistance and enhancing therapeutic outcomes, this study provides valuable insights and potential new strategies for improving the clinical management of NSCLC.

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Sialyltransferase ST3GAL4 confers osimertinib resistance and offers strategies to overcome resistance in non-small cell lung cancer

Cited by 3 publications

References 46 publications

A “One-Step” Strategy for the Global Characterization of Core-Fucosylated Glycoproteome

A “One-Step” Strategy for the Global Characterization of Core-Fucosylated Glycoproteome

Sialylation in the gut: From mucosal protection to disease pathogenesis

Xanthohumol overcomes osimertinib resistance via governing ubiquitination-modulated Ets-1 turnover

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