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Targeting Metabolic Vulnerabilities Reveals Hexokinase 2 as a Key Mediator of Resistance to Osimertinib in Non-Small Cell Lung Cancer Models

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Název: Targeting Metabolic Vulnerabilities Reveals Hexokinase 2 as a Key Mediator of Resistance to Osimertinib in Non-Small Cell Lung Cancer Models
Autoři: Yizhen Guo, Ding Huang, Yan Zhou, Maoxin Ran, Shaolin Zhang, Kin Yip Tam
Rok vydání: 2025
Témata: Biochemistry, Medicine, Microbiology, Cell Biology, Molecular Biology, Pharmacology, Developmental Biology, Cancer, Hematology, Infectious Diseases, Virology, reactive oxygen species, protein expression level, line salvage therapy, enhanced oxidative phosphorylation, acquired resistance limits, pdk1 synergistically inhibited, osir cell models, findings identified hk2, overcoming osi resistance, enhanced glycolysis, κb signaling, unexpectedly interfered, therapeutic efficacy, survival role, study reveals, single use, significant challenge, promising approach, pdk1 could
Popis: Acquired resistance to osimertinib (OSI) poses a significant challenge in the treatment of epidermal growth factor receptor mutant non-small cell lung cancer (NSCLC). Although OSI is effective as a first-line salvage therapy in T790M-positive patients following progression on first- or second-generation EGFR-TKIs (erlotinib, gefitinib, and afatinib), the inevitable development of acquired resistance limits its therapeutic efficacy. This study reveals that OSI-resistant (OSIR) NSCLC cells underwent metabolic reprogramming characterized by enhanced glycolysis and upregulation of hexokinase 2 (HK2). We demonstrated that HK2 inhibitor, benserazide, exhibited significant anticancer effects in OSIR cell models and mediated by reactive oxygen species. Our results suggested that HK2 inhibition effectively modulated the enhanced glycolysis, activated the AMPK-mTOR-autophagy axis, and unexpectedly interfered with NF-κB signaling through direct HK2-IKKβ interaction. Excitingly, the protein expression level and activity of pyruvate dehydrogenase kinase 1 (PDK1) in OSIR cells were upregulated upon HK2 inhibition, indicating a pro-survival role. Combined inhibition of HK2 and PDK1 synergistically inhibited the proliferation of OSIR cells and significantly suppressed tumor growth in an OSIR cell xenograft model, outperforming the single use of HK2 inhibitor. This combination successfully rectified aberrant glucose metabolism and enhanced oxidative phosphorylation. Our findings identified HK2 as a crucial mediator in overcoming OSI resistance and suggested that combined inhibition of HK2 and PDK1 could be a promising approach in OSIR NSCLC.
Druh dokumentu: article in journal/newspaper
Jazyk: unknown
DOI: 10.1021/acsptsci.5c00235.s001
Dostupnost: https://doi.org/10.1021/acsptsci.5c00235.s001
https://figshare.com/articles/journal_contribution/Targeting_Metabolic_Vulnerabilities_Reveals_Hexokinase_2_as_a_Key_Mediator_of_Resistance_to_Osimertinib_in_Non-Small_Cell_Lung_Cancer_Models/29503951
Rights: CC BY-NC 4.0
Přístupové číslo: edsbas.15CD83C5
Databáze: BASE
Popis
Abstrakt:Acquired resistance to osimertinib (OSI) poses a significant challenge in the treatment of epidermal growth factor receptor mutant non-small cell lung cancer (NSCLC). Although OSI is effective as a first-line salvage therapy in T790M-positive patients following progression on first- or second-generation EGFR-TKIs (erlotinib, gefitinib, and afatinib), the inevitable development of acquired resistance limits its therapeutic efficacy. This study reveals that OSI-resistant (OSIR) NSCLC cells underwent metabolic reprogramming characterized by enhanced glycolysis and upregulation of hexokinase 2 (HK2). We demonstrated that HK2 inhibitor, benserazide, exhibited significant anticancer effects in OSIR cell models and mediated by reactive oxygen species. Our results suggested that HK2 inhibition effectively modulated the enhanced glycolysis, activated the AMPK-mTOR-autophagy axis, and unexpectedly interfered with NF-κB signaling through direct HK2-IKKβ interaction. Excitingly, the protein expression level and activity of pyruvate dehydrogenase kinase 1 (PDK1) in OSIR cells were upregulated upon HK2 inhibition, indicating a pro-survival role. Combined inhibition of HK2 and PDK1 synergistically inhibited the proliferation of OSIR cells and significantly suppressed tumor growth in an OSIR cell xenograft model, outperforming the single use of HK2 inhibitor. This combination successfully rectified aberrant glucose metabolism and enhanced oxidative phosphorylation. Our findings identified HK2 as a crucial mediator in overcoming OSI resistance and suggested that combined inhibition of HK2 and PDK1 could be a promising approach in OSIR NSCLC.
DOI:10.1021/acsptsci.5c00235.s001