Kaehler Meike, von Bubnoff Nikolas, Cascorbi Ingolf, Gorantla Sivahari Prasad
Institute of Experimental and Clinical Pharmacology, University Hospital Schleswig-Holstein, Kiel, Germany.
Department of Hematology and Oncology, University Medical Center Schleswig-Holstein, Lübeck, Germany.
Front Pharmacol. 2024 Jul 22;15:1422565. doi: 10.3389/fphar.2024.1422565. eCollection 2024.
Leukemia represents a diverse group of hematopoietic neoplasms that can be classified into different subtypes based on the molecular aberration in the affected cell population. Identification of these molecular classification is required to identify specific targeted therapeutic approaches for each leukemic subtype. In general, targeted therapy approaches achieve good responses in some leukemia subgroups, however, resistance against these targeted therapies is common. In this review, we summarize molecular drug resistance biomarkers in targeted therapies in BCR::ABL1-driven chronic myeloid leukemia (CML) and JAK2-driven myeloproliferative neoplasms (MPNs). While acquisition of secondary mutations in the BCR::ABL1 kinase domain is the a common mechanism associated with TKI resistance in CML, in JAK2-driven MPNs secondary mutations in JAK2 are rare. Due to high prevalence and lack of specific therapy approaches in MPNs compared to CML, identification of crucial pathways leading to inhibitor persistence in MPN model is utterly important. In this review, we focus on different alternative signaling pathways activated in both, BCR::ABL1-mediated CML and JAK2-mediated MPNs, by combining data from and in vivo-studies that could be used as potential biomarkers of drug resistance. In a nutshell, some common similarities, especially activation of PDGFR, Ras, PI3K/Akt signaling pathways, have been demonstrated in both leukemias. In addition, induction of the nucleoprotein YBX1 was shown to be involved in TKI-resistant JAK2-mediated MPN, as well as TKI-resistant CML highlighting deubiquitinating enzymes as potential biomarkers of TKI resistance. Taken together, whole exome sequencing of cell-based or patients-derived samples are highly beneficial to define specific resistance markers. Additionally, this might be helpful for the development of novel diagnostic tools, e.g., liquid biopsy, and novel therapeutic agents, which could be used to overcome TKI resistance in molecularly distinct leukemia subtypes.
白血病是一组多样的造血系统肿瘤，可根据受累细胞群体中的分子异常分为不同亚型。识别这些分子分类对于确定每种白血病亚型的特异性靶向治疗方法至关重要。一般来说，靶向治疗方法在某些白血病亚组中取得了良好的反应，然而，对这些靶向治疗的耐药性很常见。在本综述中，我们总结了BCR::ABL1驱动的慢性髓性白血病（CML）和JAK2驱动的骨髓增殖性肿瘤（MPN）靶向治疗中的分子耐药生物标志物。虽然BCR::ABL1激酶结构域中获得继发性突变是CML中与TKI耐药相关的常见机制，但在JAK2驱动的MPN中，JAK2的继发性突变很少见。由于与CML相比，MPN的患病率高且缺乏特异性治疗方法，确定导致MPN模型中抑制剂持续存在的关键途径至关重要。在本综述中，我们通过结合来自体外和体内研究的数据，关注在BCR::ABL1介导的CML和JAK2介导的MPN中激活的不同替代信号通路，这些数据可作为耐药性的潜在生物标志物。简而言之，在两种白血病中都已证明了一些共同的相似之处，特别是PDGFR、Ras、PI3K/Akt信号通路的激活。此外，核蛋白YBX1的诱导被证明与TKI耐药的JAK2介导的MPN以及TKI耐药的CML有关，突出了去泛素化酶作为TKI耐药的潜在生物标志物。综上所述，基于细胞或患者来源样本的全外显子测序对于定义特异性耐药标志物非常有益。此外，这可能有助于开发新型诊断工具，例如液体活检，以及新型治疗药物，可用于克服分子上不同的白血病亚型中的TKI耐药性。
