Drugs in R&D · 2026
HIF-1α siRNA Enhances the Efficacy of Erlotinib in Non-small Cell Lung Cancer: A Novel Strategy to Reverse Hypoxia-Induced Drug Resistance.
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Jiang Haojie, Cai Shunhui, Zhang Xiaojun, Chen Shijie, Yue Chunyan, Yin Wu, Hu Yiqiao
Аннотация
BACKGROUND: Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality. While EGFR tyrosine kinase inhibitors (EGFR-TKIs) have improved survival, acquired resistance mediated by tumor hypoxia and HIF-1α stabilization often leads to treatment failure. This study investigated the regulatory role of HIF-1α in NSCLC drug resistance and evaluated a combined therapeutic strategy to overcome EGFR-TKI resistance.
METHODS: HIF-1α expression and downstream targets were assessed in H1975 and A549 cell lines using RT-qPCR and Western blot. Functional assays, including cell proliferation, apoptosis, invasion, lactate production, and ROS measurements, were performed following HIF-1α siRNA transfection and/or erlotinib treatment. Bioinformatics analyses of public datasets evaluated clinical relevance and pathway enrichment.
RESULTS: HIF-1α knockdown inhibited glycolysis, reduced lactate production, and alleviated hypoxia-induced oxidative stress. Combined treatment with HIF-1α siRNA and erlotinib synergistically suppressed cell proliferation, induced apoptosis, and inhibited invasion more effectively than single-agent treatments. Mechanistically, EGFR signaling positively regulated HIF-1α stability via the PI3K/AKT and MEK/ERK pathways. Bioinformatics confirmed that high HIF-1α expression correlates with poor prognosis in NSCLC patients.
CONCLUSION: Targeting HIF-1α disrupts metabolic reprogramming and hypoxia adaptation, thereby enhancing erlotinib efficacy. This combined approach highlights the therapeutic potential of HIF-1α inhibition as a novel strategy to overcome EGFR-TKI resistance in NSCLC.
METHODS: HIF-1α expression and downstream targets were assessed in H1975 and A549 cell lines using RT-qPCR and Western blot. Functional assays, including cell proliferation, apoptosis, invasion, lactate production, and ROS measurements, were performed following HIF-1α siRNA transfection and/or erlotinib treatment. Bioinformatics analyses of public datasets evaluated clinical relevance and pathway enrichment.
RESULTS: HIF-1α knockdown inhibited glycolysis, reduced lactate production, and alleviated hypoxia-induced oxidative stress. Combined treatment with HIF-1α siRNA and erlotinib synergistically suppressed cell proliferation, induced apoptosis, and inhibited invasion more effectively than single-agent treatments. Mechanistically, EGFR signaling positively regulated HIF-1α stability via the PI3K/AKT and MEK/ERK pathways. Bioinformatics confirmed that high HIF-1α expression correlates with poor prognosis in NSCLC patients.
CONCLUSION: Targeting HIF-1α disrupts metabolic reprogramming and hypoxia adaptation, thereby enhancing erlotinib efficacy. This combined approach highlights the therapeutic potential of HIF-1α inhibition as a novel strategy to overcome EGFR-TKI resistance in NSCLC.