%0 Journal Article
%T Targeting undruggable phosphatase overcomes trastuzumab resistance by inhibiting multi-oncogenic kinases.
%A Wang L
%A Lin Y
%A Yao Z
%A Babu N
%A Lin W
%A Chen C
%A Du L
%A Cai S
%A Pan Y
%A Xiong X
%A Ye Q
%A Ren H
%A Zhang D
%A Chen Y
%A Yeung SJ
%A Bremer E
%A Zhang H
%J Drug Resist Updat
%V 76
%N 0
%D 2024 Sep 14
%M 39094301
%F 22.841
%R 10.1016/j.drup.2024.101118
%X <B>OBJECTIVE: </B>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.<BR><B>METHODS: </B>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.<BR><B>RESULTS: </B>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.<BR><B>CONCLUSIONS: </B>Antibody-conjugated saRNA represents an innovative approach for targeting "undruggable" PTPs.