ORIGINAL RESEARCH article
Front. Genet.
Sec. Cancer Genetics and Oncogenomics
Volume 16 - 2025 | doi: 10.3389/fgene.2025.1593314
This article is part of the Research TopicMechanisms of Resistance to Immunotherapy and Targeted Therapy and Predictive Biomarkers in Non-small Cell Lung CancerView all 7 articles
Assembly factor for spindle microtubules (ASPM) promotes osimertinib resistance in lung cancer by increasing EGFR stability
Provisionally accepted
- 1Nanjing University of Chinese Medicine, Nanjing, China
- 2Nanjing Drum Tower Hospital, Nanjing, Jiangsu Province, China
- 3Department of Oncology, First Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu Province, China
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Background: Non-small cell lung cancer (NSCLC) represents approximately 85% of all lung malignancies, with lung adenocarcinoma (LUAD) being the predominant histologic subtype.Epidermal growth factor receptor (EGFR) mutations serve as critical therapeutic targets in NSCLC; however, resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs) remains a major clinical challenge. Recent studies highlight the need to identify molecular drivers of resistance to improve therapeutic outcomes.Method: This study analyzed tumor tissue datasets to investigate the role of the assembly factor for spindle microtubules (ASPM) in NSCLC progression and drug resistance. Bioinformatics methods revealed high expression of ASPM in tumor tissues and its association with low patient survival. Functional validation was performed using the EGFR-TKI-resistant cell line PC9 osimertinib-resistant (PC-9 OR), with ASPM-silenced models. Cellular proliferation, invasion, and EGFR protein stability analyses were conducted. Additionally, the therapeutic impact of ASPM silencing and overexpression combined with the third-generation TKI osimertinib was evaluated.Results: ASPM is significantly upregulated in NSCLC tumor tissues and is strongly associated with reduced patient survival. ASPM silencing attenuates PC-9 and PC-9 OR malignant phenotypes, including proliferation and invasion, and sensitizes resistant cells to osimertinib. In addition, inhibiting the expression of ASPM effectively reduces damage to the cell cycle and protein stability of drug-resistant cells, thereby restoring the expression and function of EGFR.This study identified ASPM as a novel regulator of EGFR-TKI resistance in NSCLC, with dual roles in promoting tumor aggressiveness and stabilizing EGFR signaling.Targeting ASPM may represent a promising therapeutic strategy to overcome EGFR-TKI resistance, enhance osimertinib efficacy, and expand treatment options for refractory NSCLC patients. These findings provide a foundation for developing ASPM-directed therapies in precision oncology.
Keywords: Non-small cell lung cancer (NSCLC), Assembly factor for spindle microtubules (ASPM), tumor invasiveness, Osimertinib, EGFR-TKI resistance, EGFR mutation
Received: 13 Mar 2025; Accepted: 08 Aug 2025.
Copyright: © 2025 Gui, Han, Yin, Cao, Zhou and Li. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Zhenyu Yin, Nanjing Drum Tower Hospital, Nanjing, 210008, Jiangsu Province, China
Peng Cao, Nanjing University of Chinese Medicine, Nanjing, China
Xin Zhou, Department of Oncology, First Affiliated Hospital, Nanjing Medical University, Nanjing, 210029, Jiangsu Province, China
Yan Li, Nanjing University of Chinese Medicine, Nanjing, China
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