Chinese clinical oncology · 2026
TP63 drives TKI resistance in EGFR-mutant lung cancer via ferroptosis inhibition.
СтатьяНазвание и аннотация: Перевод пока не подготовлен
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Li Kehan, Liu Jiane, Wang Wenjuan, Zhang Guangmin, Zhu Lina, Liu Linlin, Xu Xiaohui
Аннотация
BACKGROUND: The emergence of acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) presents a significant obstacle in the therapeutic strategy for EGFR-mutant non-small cell lung cancer (NSCLC). While secondary mutations explain some cases, adaptive resistance mechanisms involving lineage plasticity and metabolic rewiring are increasingly recognized but poorly understood. This study aimed to investigate the role of the transcription factor TP63 in mediating adaptive resistance to EGFR-TKIs, with a focus on its potential regulation of ferroptosis.
METHODS: To investigate these mechanisms, we generated osimertinib-resistant derivatives of EGFR-mutant PC9 and HCC827 cell lines. We utilized short hairpin RNA (shRNA) interference to silence TP63 and performed functional assays including cell viability, colony formation, wound-healing, and transwell invasion assays. Mechanistic insights were gained through integrated RNA sequencing (RNA-seq), immunofluorescence, and lipid peroxidation assays using BODIPY 581/591 C11.
RESULTS: We identified the transcription factor TP63 as a master regulator of adaptive resistance, showing marked upregulation in resistant cells. Although TP63 depletion did not affect basal cell viability, its loss significantly restored sensitivity to osimertinib, suppressing proliferation, clonogenic growth, and invasive potential. Transcriptomic and biochemical analyses revealed that TP63 maintains redox homeostasis by transcriptionally activating GPX4 and antioxidant gene networks. Consequently, TP63 silencing collapsed this defense system, leading to the accumulation of lipid peroxides and inducing ferroptotic cell death under drug pressure.
CONCLUSIONS: Clinically, high TP63 expression correlates with reduced overall survival in EGFR-mutant NSCLC patients. These findings define a critical TP63-GPX4 ferroptosis axis that safeguards tumor cell survival during therapeutic stress, highlighting ferroptosis induction as a potential therapeutic strategy to overcome EGFR-TKI resistance.
METHODS: To investigate these mechanisms, we generated osimertinib-resistant derivatives of EGFR-mutant PC9 and HCC827 cell lines. We utilized short hairpin RNA (shRNA) interference to silence TP63 and performed functional assays including cell viability, colony formation, wound-healing, and transwell invasion assays. Mechanistic insights were gained through integrated RNA sequencing (RNA-seq), immunofluorescence, and lipid peroxidation assays using BODIPY 581/591 C11.
RESULTS: We identified the transcription factor TP63 as a master regulator of adaptive resistance, showing marked upregulation in resistant cells. Although TP63 depletion did not affect basal cell viability, its loss significantly restored sensitivity to osimertinib, suppressing proliferation, clonogenic growth, and invasive potential. Transcriptomic and biochemical analyses revealed that TP63 maintains redox homeostasis by transcriptionally activating GPX4 and antioxidant gene networks. Consequently, TP63 silencing collapsed this defense system, leading to the accumulation of lipid peroxides and inducing ferroptotic cell death under drug pressure.
CONCLUSIONS: Clinically, high TP63 expression correlates with reduced overall survival in EGFR-mutant NSCLC patients. These findings define a critical TP63-GPX4 ferroptosis axis that safeguards tumor cell survival during therapeutic stress, highlighting ferroptosis induction as a potential therapeutic strategy to overcome EGFR-TKI resistance.