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Targeting Metabolic Vulnerabilities Reveals Hexokinase 2 as a Key Mediator of Resistance to Osimertinib in Non-Small
Yizhen Guo1, Ding Huang1, Yan Zhou1
1Faculty of Health Sciences, University of Macau, Taipa, Macau 999078, China.
Abstract:
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.
Insights
Acquired resistance to osimertinib in non-small cell lung cancer (NSCLC) can be overcome by targeting hexokinase 2 (HK2). Combined inhibition of HK2 and pyruvate dehydrogenase kinase 1 (PDK1) shows synergistic effects against resistant NSCLC.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Metabolism
Background:
- Acquired resistance to osimertinib (OSI) is a major challenge in treating epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC).
- OSI resistance is associated with metabolic reprogramming, including enhanced glycolysis and increased hexokinase 2 (HK2) expression.
- Understanding the mechanisms of OSI resistance is crucial for developing effective therapeutic strategies.
Purpose of the Study:
- To investigate the role of hexokinase 2 (HK2) in osimertinib-resistant NSCLC (OSIR NSCLC).
- To evaluate the therapeutic potential of HK2 inhibition, alone and in combination with pyruvate dehydrogenase kinase 1 (PDK1) inhibition, in OSIR NSCLC.
- To elucidate the underlying molecular mechanisms of HK2-mediated resistance and the effects of combined inhibition.
Main Methods:
- Utilized OSIR NSCLC cell models and xenograft models.
- Investigated the effects of HK2 inhibition using benserazide.
- Assessed the impact of combined HK2 and PDK1 inhibition on cancer cell proliferation, tumor growth, glucose metabolism, and signaling pathways (AMPK-mTOR-autophagy, NF-κB).
Main Results:
- OSIR NSCLC cells exhibited enhanced glycolysis and upregulated HK2.
- HK2 inhibition demonstrated anticancer effects by modulating glycolysis, activating the AMPK-mTOR-autophagy axis, and interfering with NF-κB signaling.
- Combined inhibition of HK2 and PDK1 synergistically suppressed OSIR NSCLC proliferation and tumor growth, rectifying aberrant glucose metabolism and enhancing oxidative phosphorylation.
Conclusions:
- HK2 is a critical mediator in overcoming osimertinib resistance in NSCLC.
- Combined inhibition of HK2 and PDK1 represents a promising therapeutic strategy for OSIR NSCLC.
- Targeting metabolic reprogramming, specifically HK2 and PDK1, offers a novel approach to combatting acquired resistance in NSCLC.
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