Ibrutinib Resistance Is Reduced by an Inhibitor of Fatty Acid Oxidation in Primary CLL Lymphocytes.
Ibrutinib Resistance Is Reduced by an Inhibitor of Fatty Acid Oxidation in Primary CLL Lymphocytes.
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DOI：
10.3389/fonc.2018.00411
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发表时间：
2018
影响因子：
4.7
通讯作者：
Aloyz R
中科院分区：
文献类型：
--
作者：
Galicia-Vázquez G;Aloyz R
慢性淋巴细胞性白血病（CLL）是一种不治之症，其特征在于恶性B淋巴细胞在血流（静止状态）和归巢组织（它们可以增殖的地方）中的积累。在CLL中，通过Burton酪氨酸激酶抑制剂（伊曲替尼）靶向B细胞受体信号传导已获得出色的临床结果。然而，由于耐药性或复发，不能保证完全缓解，这揭示了对CLL治疗新方法的需求。增殖性癌细胞中代谢重新布线的表征已经被应用于诊断和治疗目的，但我们对与CLL细胞相关的静止细胞代谢的了解仍然是零碎的。最近，我们报道了del11q缺失的原代CLL细胞中的谷氨酰胺代谢与del11q阴性细胞不同，使得del11q细胞对谷氨酰胺酶和糖酵解抑制剂特别敏感。在这项工作中，我们使用我们的主要CLL淋巴细胞库和干扰中心碳代谢的化合物来定义与伊鲁替尼耐药相关的代谢特征。我们观察到基础代谢物摄取差异与伊鲁替尼耐药相关，有利于谷氨酰胺摄取和catalysts。在伊鲁替尼治疗后，伊鲁替尼抗性细胞中的氧化还原平衡向NADPH积累转移，而谷氨酰胺摄取没有增加，这表明替代性代谢重新布线，例如脂肪酸氧化的激活。根据这一想法，通过CPT 1抑制（etomoxir）减少脂肪酸氧化使耐药细胞对伊鲁替尼重新敏感。我们的研究结果表明，脂肪酸氧化可以探索作为克服伊鲁替尼耐药性的目标。
Chronic Lymphocytic Leukemia (CLL) is an incurable disease, characterized by the accumulation of malignant B-lymphocytes in the blood stream (quiescent state) and homing tissues (where they can proliferate). In CLL, the targeting of B-cell receptor signaling through a Burton's tyrosine kinase inhibitor (ibrutinib) has rendered outstanding clinical results. However, complete remission is not guaranteed due to drug resistance or relapse, revealing the need for novel approaches for CLL treatment. The characterization of metabolic rewiring in proliferative cancer cells is already being applied for diagnostic and therapeutic purposes, but our knowledge of quiescent cell metabolism—relevant for CLL cells—is still fragmentary. Recently, we reported that glutamine metabolism in primary CLL cells bearing the del11q deletion is different from their del11q negative counterparts, making del11q cells especially sensitive to glutaminase and glycolysis inhibitors. In this work, we used our primary CLL lymphocyte bank and compounds interfering with central carbon metabolism to define metabolic traits associated with ibrutinib resistance. We observe a differential basal metabolite uptake linked to ibrutinib resistance, favoring glutamine uptake and catabolism. Upon ibrutinib treatment, the redox balance in ibrutinib resistant cells is shifted toward NADPH accumulation, without an increase in glutamine uptake, suggesting alternative metabolic rewiring such as the activation of fatty acid oxidation. In accordance to this idea, the curtailing of fatty acid oxidation by CPT1 inhibition (etomoxir) re-sensitized resistant cells to ibrutinib. Our results suggest that fatty acid oxidation could be explored as a target to overcome ibrutinib resistance.
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DOI：
10.1158/1078-0432.ccr-14-1088
发表时间：
2015-03-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
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