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Signal Transduction and Targeted Therapy

Signal Transduction and Targeted Therapy

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Full-length transcriptome atlas of gallbladder cancer reveals trastuzumab resistance conferred by ERBB2 alternative splicing

Published:14 February 2025 DOI: 10.1038/s41392-025-02150-w PMID: 39948369
Ziyi Wang,?Li Gao,?Ziheng Jia,?Liguo Liu,?Ao Gu,?Zhaonan Liu,?Qin Zhu,?Yichen Zuo,?Mingjie Yang,?Shijia Wang,?Jiyao Ma,?Jingyun Zhang,?Shimei Qiu,?Zhizhen Li,?Jinghan Wang,?Dongxi Xiang,?Fatao Liu,?Rong Shao,?Yanjing Li,?Maolan Li,?Wu Wei,?Yingbin Liu

Abstract

Aberrant RNA alternative splicing in cancer generates varied novel isoforms and protein variants that facilitate cancer progression. Here, we employed the advanced long-read full-length transcriptome sequencing on gallbladder normal tissues, tumors, and cell lines to establish a comprehensive full-length gallbladder transcriptomic atlas. It is of note that receptor tyrosine kinases were one of the most dynamic components with highly variable transcript, with Erb-B2 receptor tyrosine kinase 2 (ERBB2) as a prime representative. A novel transcript, designated ERBB2 i14e, was identified for encoding a novel functional protein, and its protein expression was elevated in gallbladder cancer and strongly associated with worse prognosis. With the regulation of splicing factors ESRP1/2, ERBB2 i14e was alternatively spliced from intron 14 and the encoded i14e peptide was proved to facilitate the interaction with ERBB3 and downstream signaling activation of AKT. ERBB2 i14e was inducible and its expression attenuated anti-ERBB2 treatment efficacy in tumor xenografts. Further studies with patient derived xenografts models validated that ERBB2 i14e blockage with antisense oligonucleotide enhanced the tumor sensitivity to trastuzumab and its drug conjugates. Overall, this study provides a gallbladder specific long-read transcriptome profile and discovers a novel mechanism of trastuzumab resistance, thus ultimately devising strategies to improve trastuzumab therapy.

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Materials
Procduct Name CAS Molecular Formula Supplier Price
Trastuzumab 180288-69-1 C10H14N6O5 154 suppliers Inquiry
Trastuzumab 180288-69-1 C10H14N6O5 154 suppliers Inquiry
Trastuzumab 180288-69-1 C10H14N6O5 154 suppliers Inquiry
Trastuzumab 180288-69-1 C10H14N6O5 154 suppliers Inquiry
Trastuzumab 180288-69-1 - Inquiry
Trastuzumab 180288-69-1 - Inquiry
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