{Reference Type}: Journal Article
{Title}: Targeting undruggable phosphatase overcomes trastuzumab resistance by inhibiting multi-oncogenic kinases.
{Author}: Wang L;Lin Y;Yao Z;Babu N;Lin W;Chen C;Du L;Cai S;Pan Y;Xiong X;Ye Q;Ren H;Zhang D;Chen Y;Yeung SJ;Bremer E;Zhang H;
{Journal}: Drug Resist Updat
{Volume}: 76
{Issue}: 0
{Year}: 2024 Sep 14
{Factor}: 22.841
{DOI}: 10.1016/j.drup.2024.101118
{Abstract}: <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.