TP53 mutation promotes sunitinib resistance in gallbladder cancer via the ARHGEF7-AS2/miR-326/AXL pathway
5 affiliations
- 1Department of Biliary-Pancreatic Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
- 2Department of Systems Biology, Beckman Research Institute, City of Hope, Monrovia, CA 91016, USA
- 3Department of Urology, Fudan University Shanghai Cancer Center, Shanghai 200032, China
- 4The Core Laboratory in Medical Center of Clinical Research, Shanghai Ninth People's Hospital, State Key Laboratory of Medical Genomics, Shanghai Jiao Tong University School of Medicine, Shanghai 200125, China
- 5Department of Pathology, Mount Sinai West/Morningside Hospitals, New York, NY 10025, USA
Abstract
Gallbladder cancer (GBC) is an aggressive digestive malignancy with poor prognosis and frequent treatment resistance. Aberrant receptor tyrosine kinase (RTK) signaling is common in GBC and supports use of RTK inhibitors (RTKis) such as sunitinib, yet clinical responses remain limited and the mechanisms driving resistance are unclear. In this study, we utilized patient-derived xenograft (PDX) models of GBC and conducted RNA microarray profiling alongside whole-exome sequencing to identify differentially expressed long non-coding RNAs (lncRNAs) and gene mutations associated with sunitinib resistance. Our findings reveal a novel resistance mechanism whereby TP53 loss impairs its binding to the transcription factor SP1, resulting in SP1-mediated transcriptional activation of the lncRNA ARHGEF7-AS2. Upregulation of ARHGEF7-AS2 functions as a competing endogenous RNA (ceRNA) that sequesters miR-326, thereby relieving repression of its target gene AXL and activating the downstream AKT signaling cascade. This regulatory axis promotes resistance to sunitinib in GBC cells. Importantly, inhibition of ARHGEF7-AS2 or pharmacological blockade of the AXL/AKT pathway restored sunitinib sensitivity, underscoring the therapeutic potential of targeting this pathway. Collectively, our study identifies a previously unrecognized TP53/ARHGEF7-AS2/miR-326/AXL signaling axis that contributes to sunitinib resistance in GBC, providing new mechanistic insights and potential avenues for therapeutic intervention in advanced disease.
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BibTeX
@article{yang2026tp53,
title = {{TP53 mutation promotes sunitinib resistance in gallbladder cancer via the ARHGEF7-AS2/miR-326/AXL pathway}},
author = {Linhua Yang and Ming Zhan and Ruifeng Yang and Miaomiao Guo and Min He and Yixiang Gu and Yang Zhang and Zhilian Jia and Xiaohua Huang and Bingyu Li and Hui Wang and Ruimeng Yang and Yingbin Liu},
journal = {Acta pharmaceutica Sinica. B},
year = {2026},
month = aug,
doi = {10.1016/j.apsb.2026.08.019},
url = {https://europepmc.org/article/PMC/PMC13729714},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - TP53 mutation promotes sunitinib resistance in gallbladder cancer via the ARHGEF7-AS2/miR-326/AXL pathway
AU - Linhua Yang
AU - Ming Zhan
AU - Ruifeng Yang
AU - Miaomiao Guo
AU - Min He
AU - Yixiang Gu
AU - Yang Zhang
AU - Zhilian Jia
AU - Xiaohua Huang
AU - Bingyu Li
AU - Hui Wang
AU - Ruimeng Yang
AU - Yingbin Liu
PY - 2026
DA - 2026/08/25
JO - Acta pharmaceutica Sinica. B
DO - 10.1016/j.apsb.2026.08.019
UR - https://europepmc.org/article/PMC/PMC13729714
AB - Gallbladder cancer (GBC) is an aggressive digestive malignancy with poor prognosis and frequent treatment resistance. Aberrant receptor tyrosine kinase (RTK) signaling is common in GBC and supports use of RTK inhibitors (RTKis) such as sunitinib, yet clinical responses remain limited and the mechanisms driving resistance are unclear. In this study, we utilized patient-derived xenograft (PDX) models of GBC and conducted RNA microarray profiling alongside whole-exome sequencing to identify differentially expressed long non-coding RNAs (lncRNAs) and gene mutations associated with sunitinib resistance. Our findings reveal a novel resistance mechanism whereby TP53 loss impairs its binding to the transcription factor SP1, resulting in SP1-mediated transcriptional activation of the lncRNA ARHGEF7-AS2. Upregulation of ARHGEF7-AS2 functions as a competing endogenous RNA (ceRNA) that sequesters miR-326, thereby relieving repression of its target gene AXL and activating the downstream AKT signaling cascade. This regulatory axis promotes resistance to sunitinib in GBC cells. Importantly, inhibition of ARHGEF7-AS2 or pharmacological blockade of the AXL/AKT pathway restored sunitinib sensitivity, underscoring the therapeutic potential of targeting this pathway. Collectively, our study identifies a previously unrecognized TP53/ARHGEF7-AS2/miR-326/AXL signaling axis that contributes to sunitinib resistance in GBC, providing new mechanistic insights and potential avenues for therapeutic intervention in advanced disease.
SN - 2211-3835
SN - 2211-3843
ER -