Lu Wang , Yusheng Lin , Zhimeng Yao , Nipun Babu , Wan Lin , Chaoying Chen , Liang Du , Songwang Cai , Yunlong Pan , Xiao Xiong , Qiantao Ye , Hongzheng Ren , Dianzheng Zhang , Yexi Chen , Sai-Ching Jim Yeung , Edwin Bremer , Hao Zhang
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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.</p></div><div><h3>Results</h3><p>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.</p></div><div><h3>Conclusions</h3><p>Antibody-conjugated saRNA represents an innovative approach for targeting “undruggable” PTPs.</p></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"76 ","pages":"Article 101118"},"PeriodicalIF":15.8000,"publicationDate":"2024-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1368764624000761/pdfft?md5=143e4f02d2f1e140376cf2e139f7759f&pid=1-s2.0-S1368764624000761-main.pdf","citationCount":"0","resultStr":"{\"title\":\"Targeting undruggable phosphatase overcomes trastuzumab resistance by inhibiting multi-oncogenic kinases\",\"authors\":\"Lu Wang , Yusheng Lin , Zhimeng Yao , Nipun Babu , Wan Lin , Chaoying Chen , Liang Du , Songwang Cai , Yunlong Pan , Xiao Xiong , Qiantao Ye , Hongzheng Ren , Dianzheng Zhang , Yexi Chen , Sai-Ching Jim Yeung , Edwin Bremer , Hao Zhang\",\"doi\":\"10.1016/j.drup.2024.101118\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><h3>Aims</h3><p>Resistance to targeted therapy is one of the critical obstacles in cancer management. 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Targeting undruggable phosphatase overcomes trastuzumab resistance by inhibiting multi-oncogenic kinases
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.
期刊介绍:
Drug Resistance Updates serves as a platform for publishing original research, commentary, and expert reviews on significant advancements in drug resistance related to infectious diseases and cancer. It encompasses diverse disciplines such as molecular biology, biochemistry, cell biology, pharmacology, microbiology, preclinical therapeutics, oncology, and clinical medicine. The journal addresses both basic research and clinical aspects of drug resistance, providing insights into novel drugs and strategies to overcome resistance. Original research articles are welcomed, and review articles are authored by leaders in the field by invitation.
Articles are written by leaders in the field, in response to an invitation from the Editors, and are peer-reviewed prior to publication. Articles are clear, readable, and up-to-date, suitable for a multidisciplinary readership and include schematic diagrams and other illustrations conveying the major points of the article. The goal is to highlight recent areas of growth and put them in perspective.
*Expert reviews in clinical and basic drug resistance research in oncology and infectious disease
*Describes emerging technologies and therapies, particularly those that overcome drug resistance
*Emphasises common themes in microbial and cancer research