SUMOylation counteracts ubiquitination to stabilize ANKRD1 and promote osimertinib resistance in lung adenocarcinoma
- 1The Third Affiliated Hospital of Kunming Medical University, Yunnan Cancer Hospital, Yunnan Cancer Center
- 2West China Hospital, West China School of Medicine, Sichuan University
- 3Haiyuan College of Kunming Medical University
Abstract
Introduction: Acquired resistance to osimertinib remains a major challenge in the treatment of EGFR-mutant lung adenocarcinoma (LUAD), yet the contribution of stress-responsive protein homeostasis to resistance remains incompletely understood. This study aimed to investigate the role and regulatory mechanisms of ankyrin repeat domain 1 (ANKRD1) in acquired osimertinib resistance.
Methods: Public transcriptomic datasets and machine learning-based feature selection were integrated with osimertinib-resistant LUAD cell models, paired clinical specimens, RNA sequencing, biochemical and molecular assays, functional rescue experiments, and in vivo tumor models to investigate the role of ANKRD1 and its upstream and downstream regulatory mechanisms in osimertinib resistance.
Results: ANKRD1 was upregulated in osimertinib-resistant LUAD models and promoted tumor cell survival under therapeutic pressure. Mechanistically, zinc finger protein 593 (ZNF593) interacted with ANKRD1 and facilitated its SUMO1-dependent modification, which was associated with reduced ubiquitin-mediated degradation and enhanced ANKRD1 protein stability. Stabilized ANKRD1 subsequently promoted MERTK expression and sustained downstream AKT signaling, thereby supporting tumor cell survival under osimertinib pressure. Furthermore, K41 emerged as a critical regulatory residue, as K41R simultaneously impaired ANKRD1 SUMOylation, ubiquitination, and interaction with ZNF593, accompanied by attenuated downstream signaling and resistance phenotypes. These findings suggest that K41 plays an important role in coordinating ANKRD1 post-translational regulation and its interaction with ZNF593.
Discussion: Our study identifies a proteostasis-related mechanism contributing to acquired osimertinib resistance and provides mechanistic insight into the ZNF593–ANKRD1–MERTK axis in EGFR-mutant LUAD. These findings support further investigation of this regulatory axis as a potential vulnerability in osimertinib-resistant LUAD.
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BibTeX
@article{fan2026sumoylation,
title = {{SUMOylation counteracts ubiquitination to stabilize ANKRD1 and promote osimertinib resistance in lung adenocarcinoma}},
author = {BiaoFeng Fan and Qing Lei and HaoNan Wang and ChenJun Xin and XuanCheng Li and XiRui Zhu and JinXiang Kong and SiQi Xie and JianLiang Shang and ZuYang Li and Chao Deng and DongJin Lv and WeiWei Wang},
journal = {Frontiers in Oncology},
year = {2026},
month = oct,
doi = {10.3389/fonc.2026.1960448},
url = {https://www.frontiersin.org/articles/10.3389/fonc.2026.1960448/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - SUMOylation counteracts ubiquitination to stabilize ANKRD1 and promote osimertinib resistance in lung adenocarcinoma
AU - BiaoFeng Fan
AU - Qing Lei
AU - HaoNan Wang
AU - ChenJun Xin
AU - XuanCheng Li
AU - XiRui Zhu
AU - JinXiang Kong
AU - SiQi Xie
AU - JianLiang Shang
AU - ZuYang Li
AU - Chao Deng
AU - DongJin Lv
AU - WeiWei Wang
PY - 2026
DA - 2026/10/22
JO - Frontiers in Oncology
DO - 10.3389/fonc.2026.1960448
UR - https://www.frontiersin.org/articles/10.3389/fonc.2026.1960448/full
AB - Introduction: Acquired resistance to osimertinib remains a major challenge in the treatment of EGFR-mutant lung adenocarcinoma (LUAD), yet the contribution of stress-responsive protein homeostasis to resistance remains incompletely understood. This study aimed to investigate the role and regulatory mechanisms of ankyrin repeat domain 1 (ANKRD1) in acquired osimertinib resistance. Methods: Public transcriptomic datasets and machine learning-based feature selection were integrated with osimertinib-resistant LUAD cell models, paired clinical specimens, RNA sequencing, biochemical and molecular assays, functional rescue experiments, and in vivo tumor models to investigate the role of ANKRD1 and its upstream and downstream regulatory mechanisms in osimertinib resistance. Results: ANKRD1 was upregulated in osimertinib-resistant LUAD models and promoted tumor cell survival under therapeutic pressure. Mechanistically, zinc finger protein 593 (ZNF593) interacted with ANKRD1 and facilitated its SUMO1-dependent modification, which was associated with reduced ubiquitin-mediated degradation and enhanced ANKRD1 protein stability. Stabilized ANKRD1 subsequently promoted MERTK expression and sustained downstream AKT signaling, thereby supporting tumor cell survival under osimertinib pressure. Furthermore, K41 emerged as a critical regulatory residue, as K41R simultaneously impaired ANKRD1 SUMOylation, ubiquitination, and interaction with ZNF593, accompanied by attenuated downstream signaling and resistance phenotypes. These findings suggest that K41 plays an important role in coordinating ANKRD1 post-translational regulation and its interaction with ZNF593. Discussion: Our study identifies a proteostasis-related mechanism contributing to acquired osimertinib resistance and provides mechanistic insight into the ZNF593–ANKRD1–MERTK axis in EGFR-mutant LUAD. These findings support further investigation of this regulatory axis as a potential vulnerability in osimertinib-resistant LUAD.
SN - 2234-943X
ER -