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

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

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

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

Research output: Contribution to journal › Article › peer-review

Abstract

AIMS: Resistance to targeted therapy is one of the critical obstacles in cancer management. Resistance to trastuzumab frequently develops in the treatment for HER2

METHODS: Four public datasets were used to screen PTP candidates in relation to trastuzumab responsiveness in HER2

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.

Original language	American English
Journal	Drug Resistance Updates
Volume	76
DOIs	https://doi.org/10.1016/j.drup.2024.101118
State	Published - Sep 1 2024

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Cite this

@article{0b0154536b9d4465a7d857ff7837fe64,

title = "Targeting undruggable phosphatase overcomes trastuzumab resistance by inhibiting multi-oncogenic kinases.",

abstract = "AIMS: Resistance to targeted therapy is one of the critical obstacles in cancer management. Resistance to trastuzumab frequently develops in the treatment for HER2 METHODS: Four public datasets were used to screen PTP candidates in relation to trastuzumab responsiveness in HER2 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.",

author = "Lu Wang and Yusheng Lin and Zhimeng Yao and Nipun Babu and Wan Lin and Chaoying Chen and Liang Du and Songwang Cai and Yunlong Pan and Xiao Xiong and Qiantao Ye and Hongzheng Ren and Dianzheng Zhang and Yexi Chen and Yeung, {Sai-Ching Jim} and Edwin Bremer and Hao Zhang",

year = "2024",

month = sep,

day = "1",

doi = "10.1016/j.drup.2024.101118",

language = "American English",

volume = "76",

journal = "Drug Resistance Updates",

}

TY - JOUR

T1 - Targeting undruggable phosphatase overcomes trastuzumab resistance by inhibiting multi-oncogenic kinases.

AU - Wang, Lu

AU - Lin, Yusheng

AU - Yao, Zhimeng

AU - Babu, Nipun

AU - Lin, Wan

AU - Chen, Chaoying

AU - Du, Liang

AU - Cai, Songwang

AU - Pan, Yunlong

AU - Xiong, Xiao

AU - Ye, Qiantao

AU - Ren, Hongzheng

AU - Zhang, Dianzheng

AU - Chen, Yexi

AU - Yeung, Sai-Ching Jim

AU - Bremer, Edwin

AU - Zhang, Hao

PY - 2024/9/1

Y1 - 2024/9/1

N2 - AIMS: Resistance to targeted therapy is one of the critical obstacles in cancer management. Resistance to trastuzumab frequently develops in the treatment for HER2 METHODS: Four public datasets were used to screen PTP candidates in relation to trastuzumab responsiveness in HER2 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.

AB - AIMS: Resistance to targeted therapy is one of the critical obstacles in cancer management. Resistance to trastuzumab frequently develops in the treatment for HER2 METHODS: Four public datasets were used to screen PTP candidates in relation to trastuzumab responsiveness in HER2 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.

U2 - 10.1016/j.drup.2024.101118

DO - 10.1016/j.drup.2024.101118

M3 - Article

C2 - 39094301

VL - 76

JO - Drug Resistance Updates

JF - Drug Resistance Updates

ER -