Targeting undruggable phosphatase overcomes trastuzumab resistance by inhibiting multi-oncogenic kinases.

Autor: Wang L; Department of General Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, China; State Key Laboratory of Bioactive Molecules and Druggability Assessment, MOE Key Laboratory of Tumor Molecular Biology, and Institute of Precision Cancer Medicine and Pathology, School of Medicine, Jinan University, Guangzhou, China; Zhuhai Institute of Jinan University, Zhuhai, China., Lin Y; State Key Laboratory of Bioactive Molecules and Druggability Assessment, MOE Key Laboratory of Tumor Molecular Biology, and Institute of Precision Cancer Medicine and Pathology, School of Medicine, Jinan University, Guangzhou, China; Zhuhai Institute of Jinan University, Zhuhai, China; Department of Thoracic Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, China; Department of Hematology, University of Groningen, University Medical Center Groningen, the Netherlands; Shantou University Medical College, Shantou, China., Yao Z; State Key Laboratory of Bioactive Molecules and Druggability Assessment, MOE Key Laboratory of Tumor Molecular Biology, and Institute of Precision Cancer Medicine and Pathology, School of Medicine, Jinan University, Guangzhou, China; Zhuhai Institute of Jinan University, Zhuhai, China; Department of Urology Surgery, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, China., Babu N; Shantou University Medical College, Shantou, China., Lin W; Shantou University Medical College, Shantou, China., Chen C; Shantou University Medical College, Shantou, China., Du L; State Key Laboratory of Bioactive Molecules and Druggability Assessment, MOE Key Laboratory of Tumor Molecular Biology, and Institute of Precision Cancer Medicine and Pathology, School of Medicine, Jinan University, Guangzhou, China; Zhuhai Institute of Jinan University, Zhuhai, China., Cai S; Department of Thoracic Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, China., Pan Y; Department of General Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, China., Xiong X; State Key Laboratory of Bioactive Molecules and Druggability Assessment, MOE Key Laboratory of Tumor Molecular Biology, and Institute of Precision Cancer Medicine and Pathology, School of Medicine, Jinan University, Guangzhou, China; Zhuhai Institute of Jinan University, Zhuhai, China., Ye Q; State Key Laboratory of Bioactive Molecules and Druggability Assessment, MOE Key Laboratory of Tumor Molecular Biology, and Institute of Precision Cancer Medicine and Pathology, School of Medicine, Jinan University, Guangzhou, China; Zhuhai Institute of Jinan University, Zhuhai, China., Ren H; Department of Pathology, Gongli Hospital of Shanghai Pudong New Area, Shanghai, China; Department of Pathology, Heping Hospital, Changzhi Medical College, Changzhi, China., Zhang D; Department of Biomedical Sciences, Philadelphia College of Osteopathic Medicine, Philadelphia, PA, USA., Chen Y; Department of Thyroid, Breast and Hernia Surgery, The Second Affiliated Hospital of Shantou University Medical College, Shantou, China., Yeung SJ; Department of Emergency Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Endocrine Neoplasia and Hormonal Disorders, University of Texas MD Anderson Cancer Center, Houston, TX, USA., Bremer E; Department of Hematology, University of Groningen, University Medical Center Groningen, the Netherlands., Zhang H; Department of Pathology, Gongli Hospital of Shanghai Pudong New Area, Shanghai, China; State Key Laboratory of Bioactive Molecules and Druggability Assessment, MOE Key Laboratory of Tumor Molecular Biology, and Institute of Precision Cancer Medicine and Pathology, School of Medicine, Jinan University, Guangzhou, China; Department of General Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, China; Department of Thyroid, Breast and Hernia Surgery, The Second Affiliated Hospital of Shantou University Medical College, Shantou, China. Electronic address: haolabcancercenter@163.com.
Jazyk: angličtina
Zdroj: Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy [Drug Resist Updat] 2024 Sep; Vol. 76, pp. 101118. Date of Electronic Publication: 2024 Jul 14.
DOI: 10.1016/j.drup.2024.101118
Abstrakt: Aims: Resistance to targeted therapy is one of the critical obstacles in cancer management. Resistance to trastuzumab frequently develops in the treatment for HER2 + cancers. The role of protein tyrosine phosphatases (PTPs) in trastuzumab resistance is not well understood. In this study, we aim to identify pivotal PTPs affecting trastuzumab resistance and devise a novel counteracting strategy.
Methods: Four public datasets were used to screen PTP candidates in relation to trastuzumab responsiveness in HER2 + breast cancer. Tyrosine kinase (TK) arrays were used to identify kinases that linked to protein tyrosine phosphate receptor type O (PTPRO)-enhanced trastuzumab sensitivity. The efficacy of small activating RNA (saRNA) in trastuzumab-conjugated silica nanoparticles was tested for PTPRO upregulation and resistance mitigation in cell models, a transgenic mouse model, and human cancer cell line-derived xenograft models.
Results: PTPRO was identified as the key PTP which influences trastuzumab responsiveness and patient survival. PTPRO de-phosphorated several TKs, including the previously overlooked substrate ERBB3, thereby inhibiting multiple oncogenic pathways associated with drug resistance. Notably, PTPRO, previously deemed "undruggable," was effectively upregulated by saRNA-loaded nanoparticles. The upregulated PTPRO simultaneously inhibited ERBB3, ERBB2, and downstream SRC signaling pathways, thereby counteracting trastuzumab resistance.
Conclusions: Antibody-conjugated saRNA represents an innovative approach for targeting "undruggable" PTPs.
Competing Interests: Declaration of Competing Interest Dr. Yeung was on an advisory panel for Salix Pharmaceuticals (Bridgewater, New Jersey, USA). The other authors declare no competing interests.
(Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)
Databáze: MEDLINE
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