Komza Monika, Khatun Jesminara, Gelles Jesse D, Trotta Andrew P, Abraham-Enachescu Ioana, Henao Juan, Elsaadi Ahmed, Kotini Andriana G, Clementelli Cara, Arandela JoAnn, Ghaity-Beckley Sebastian El, Barua Agneesh, Chen Yiyang, Berisa Mirela, Marcellino Bridget K, Papapetrou Eirini P, Poyurovsky Masha V, Chipuk Jerry Edward
Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.
The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.
Cell Commun Signal. 2025 Jan 25;23(1):47. doi: 10.1186/s12964-025-02044-y.
One hallmark of cancer is the upregulation and dependency on glucose metabolism to fuel macromolecule biosynthesis and rapid proliferation. Despite significant pre-clinical effort to exploit this pathway, additional mechanistic insights are necessary to prioritize the diversity of metabolic adaptations upon acute loss of glucose metabolism. Here, we investigated a potent small molecule inhibitor to Class I glucose transporters, KL-11743, using glycolytic leukemia cell lines and patient-based model systems. Our results reveal that while several metabolic adaptations occur in response to acute glucose uptake inhibition, the most critical is increased mitochondrial oxidative phosphorylation. KL-11743 treatment efficiently blocks the majority of glucose uptake and glycolysis, yet markedly increases mitochondrial respiration via enhanced Complex I function. Compared to partial glucose uptake inhibition, dependency on mitochondrial respiration is less apparent suggesting robust blockage of glucose uptake is essential to create a metabolic vulnerability. When wild-type and oncogenic RAS patient-derived induced pluripotent stem cell acute myeloid leukemia (AML) models were examined, KL-11743 mediated induction of mitochondrial respiration and dependency for survival associated with oncogenic RAS. Furthermore, we examined the therapeutic potential of these observations by treating a cohort of primary AML patient samples with KL-11743 and witnessed similar dependency on mitochondrial respiration for sustained cellular survival. Together, these data highlight conserved adaptations to acute glucose uptake inhibition in diverse leukemic models and AML patient samples, and position mitochondrial respiration as a key determinant of treatment success.
癌症的一个标志是葡萄糖代谢上调并依赖其为大分子生物合成和快速增殖提供能量。尽管在临床前为利用这一途径付出了巨大努力，但仍需要更多的机制性见解来确定葡萄糖代谢急性丧失后代谢适应多样性的优先级。在这里，我们使用糖酵解白血病细胞系和基于患者的模型系统，研究了一种针对I类葡萄糖转运蛋白的强效小分子抑制剂KL-11743。我们的结果表明，虽然急性葡萄糖摄取抑制会引发多种代谢适应，但最关键的是线粒体氧化磷酸化增加。KL-11743处理有效阻断了大部分葡萄糖摄取和糖酵解，但通过增强复合体I功能显著增加了线粒体呼吸。与部分葡萄糖摄取抑制相比，对线粒体呼吸的依赖性不太明显，这表明强大的葡萄糖摄取阻断对于制造代谢脆弱性至关重要。当检查野生型和致癌RAS患者来源的诱导多能干细胞急性髓系白血病（AML）模型时，KL-11743介导的线粒体呼吸诱导以及对与致癌RAS相关的生存依赖性。此外，我们通过用KL-11743治疗一组原发性AML患者样本，研究了这些观察结果的治疗潜力，并目睹了对线粒体呼吸的类似依赖性以维持细胞存活。总之，这些数据突出了在不同白血病模型和AML患者样本中对急性葡萄糖摄取抑制的保守适应，并将线粒体呼吸定位为治疗成功的关键决定因素。
