Mostazo Miriam G Contreras, Kurrle Nina, Casado Marta, Fuhrmann Dominik, Alshamleh Islam, Häupl Björn, Martín-Sanz Paloma, Brüne Bernhard, Serve Hubert, Schwalbe Harald, Schnütgen Frank, Marin Silvia, Cascante Marta
Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, Universitat de Barcelona, 08028 Barcelona, Spain.
Institute of Biomedicine of University of Barcelona, 08028 Barcelona, Spain.
Cancers (Basel). 2020 Nov 19;12(11):3443. doi: 10.3390/cancers12113443.
Tyrosine kinase inhibitors (TKIs) are currently the standard chemotherapeutic agents for the treatment of chronic myeloid leukemia (CML). However, due to TKI resistance acquisition in CML patients, identification of new vulnerabilities is urgently required for a sustained response to therapy. In this study, we have investigated metabolic reprogramming induced by TKIs independent of BCR-ABL1 alterations. Proteomics and metabolomics profiling of imatinib-resistant CML cells (ImaR) was performed. KU812 ImaR cells enhanced pentose phosphate pathway, glycogen synthesis, serine-glycine-one-carbon metabolism, proline synthesis and mitochondrial respiration compared with their respective syngeneic parental counterparts. Moreover, the fact that only 36% of the main carbon sources were utilized for mitochondrial respiration pointed to glycerol-phosphate shuttle as mainly contributors to mitochondrial respiration. In conclusion, CML cells that acquire TKIs resistance present a severe metabolic reprogramming associated with an increase in metabolic plasticity needed to overcome TKI-induced cell death. Moreover, this study unveils that KU812 Parental and ImaR cells viability can be targeted with metabolic inhibitors paving the way to propose novel and promising therapeutic opportunities to overcome TKI resistance in CML.
酪氨酸激酶抑制剂（TKIs）目前是治疗慢性粒细胞白血病（CML）的标准化疗药物。然而，由于CML患者会产生TKI耐药性，因此迫切需要确定新的脆弱点以实现持续的治疗反应。在本研究中，我们研究了由TKIs诱导的、独立于BCR-ABL1改变的代谢重编程。我们对伊马替尼耐药的CML细胞（ImaR）进行了蛋白质组学和代谢组学分析。与各自同基因的亲代细胞相比，KU812 ImaR细胞增强了磷酸戊糖途径、糖原合成、丝氨酸-甘氨酸-一碳代谢、脯氨酸合成和线粒体呼吸。此外，仅36%的主要碳源用于线粒体呼吸这一事实表明，磷酸甘油穿梭主要促进了线粒体呼吸。总之，获得TKI耐药性的CML细胞呈现出严重的代谢重编程，这与克服TKI诱导的细胞死亡所需的代谢可塑性增加有关。此外，本研究表明，KU812亲代细胞和ImaR细胞的活力可以用代谢抑制剂来靶向，为提出克服CML中TKI耐药性的新的、有前景的治疗机会铺平了道路。
