Quantitative proteomics profiling reveals the inhibition of trastuzumab antitumor efficacy by phosphorylated RPS6 in gastric carcinoma.

Autor: Hu CT; Department of Pathology, Faculty of Basic Medicine, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Institutes of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China., Pei SJ; School of Public Health, Peking University, Beijing, 100191, People's Republic of China.; Department of Mathematical Sciences, Tsinghua University, Beijing, 100084, People's Republic of China., Wang JL; Department of Pathology, Faculty of Basic Medicine, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Institutes of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China., Zu LD; Department of Pathology, Faculty of Basic Medicine, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Institutes of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China., Shen WW; Department of Pathology, Faculty of Basic Medicine, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Institutes of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China., Yuan L; Pathology Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China., Gao F; Pathology Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China., Jiang LR; Pathology Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China., Yau SS; Yanqi Lake Beijing Institute of Mathematical Sciences and Applications (BIMSA), Huairou District, Beijing, 101400, People's Republic of China. yau@uic.edu.; Department of Mathematical Sciences, Tsinghua University, Beijing, 100084, People's Republic of China. yau@uic.edu., Fu GH; Department of Pathology, Faculty of Basic Medicine, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Institutes of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China. guohuifu@shsmu.edu.cn.
Jazyk: angličtina
Zdroj: Cancer chemotherapy and pharmacology [Cancer Chemother Pharmacol] 2023 Nov; Vol. 92 (5), pp. 341-355. Date of Electronic Publication: 2023 Jul 28.
DOI: 10.1007/s00280-023-04571-2
Abstrakt: Background: The anti-HER2 antibody trastuzumab is a standard treatment for gastric carcinoma with HER2 overexpression, but not all patients benefit from treatment with HER2-targeted therapies due to intrinsic and acquired resistance. Thus, more precise predictors for selecting patients to receive trastuzumab therapy are urgently needed.
Methods: We applied mass spectrometry-based proteomic analysis to 38 HER2-positive gastric tumor biopsies from 19 patients pretreated with trastuzumab (responders n = 10; nonresponders, n = 9) to identify factors that may influence innate sensitivity or resistance to trastuzumab therapy and validated the results in tumor cells and patient samples.
Results: Statistical analyses revealed significantly lower phosphorylated ribosomal S6 (p-RPS6) levels in responders than nonresponders, and this downregulation was associated with a durable response and better overall survival after anti-HER2 therapy. High p-RPS6 levels could trigger AKT/mTOR/RPS6 signaling and inhibit trastuzumab antitumor efficacy in nonresponders. We demonstrated that RPS6 phosphorylation inhibitors in combination with trastuzumab effectively suppressed HER2-positive GC cell survival through the inhibition of the AKT/mTOR/RPS6 axis.
Conclusions: Our findings provide for the first time a detailed proteomics profile of current protein alterations in patients before anti-HER2 therapy and present a novel and optimal predictor for the response to trastuzumab treatment. HER2-positive GC patients with low expression of p-RPS6 are more likely to benefit from trastuzumab therapy than those with high expression. However, those with high expression of p-RPS6 may benefit from trastuzumab in combination with RPS6 phosphorylation inhibitors.
(© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)
Databáze: MEDLINE
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