Buono Roberta, Alhaddad Muneera, Fruman David A
Department of Molecular Biology & Biochemistry, University of California, Irvine, Irvine, CA, United States.
Hematology/Oncology Fellowship Program, CHOC Children's Hospital, Orange, CA, United States.
Front Oncol. 2023 Apr 14;13:1162694. doi: 10.3389/fonc.2023.1162694. eCollection 2023.
High-risk subtypes of B-cell acute lymphoblastic leukemia (B-ALL) are frequently associated with aberrant activation of tyrosine kinases (TKs). These include Ph+ B-ALL driven by BCR-ABL, and Ph-like B-ALL that carries other chromosomal rearrangements and/or gene mutations that activate TK signaling. Currently, the tyrosine kinase inhibitor (TKI) dasatinib is added to chemotherapy as standard of care in Ph+ B-ALL, and TKIs are being tested in clinical trials for Ph-like B-ALL. However, growth factors and nutrients in the leukemia microenvironment can support cell cycle and survival even in cells treated with TKIs targeting the driving oncogene. These stimuli converge on the kinase mTOR, whose elevated activity is associated with poor prognosis. In preclinical models of Ph+ and Ph-like B-ALL, mTOR inhibitors strongly enhance the anti-leukemic efficacy of TKIs. Despite this strong conceptual basis for targeting mTOR in B-ALL, the first two generations of mTOR inhibitors tested clinically (rapalogs and mTOR kinase inhibitors) have not demonstrated a clear therapeutic window. The aim of this review is to introduce new therapeutic strategies to the management of Ph-like B-ALL. We discuss novel approaches to targeting mTOR in B-ALL with potential to overcome the limitations of previous mTOR inhibitor classes. One approach is to apply third-generation bi-steric inhibitors that are selective for mTOR complex-1 (mTORC1) and show preclinical efficacy with intermittent dosing. A distinct, non-pharmacological approach is to use nutrient restriction to target signaling and metabolic dependencies in malignant B-ALL cells. These two new approaches could potentiate TKI efficacy in Ph-like leukemia and improve survival.
B细胞急性淋巴细胞白血病（B-ALL）的高危亚型常与酪氨酸激酶（TKs）的异常激活相关。这些亚型包括由BCR-ABL驱动的Ph+ B-ALL，以及携带其他染色体重排和/或基因突变从而激活TK信号的Ph样B-ALL。目前，酪氨酸激酶抑制剂（TKI）达沙替尼作为Ph+ B-ALL的标准治疗方案被添加到化疗中，并且TKI正在针对Ph样B-ALL进行临床试验。然而，白血病微环境中的生长因子和营养物质即使在使用靶向驱动癌基因的TKI治疗的细胞中也能支持细胞周期和存活。这些刺激作用于激酶mTOR，其活性升高与预后不良相关。在Ph+和Ph样B-ALL的临床前模型中，mTOR抑制剂可显著增强TKI的抗白血病疗效。尽管在B-ALL中靶向mTOR有很强的理论基础，但临床测试的前两代mTOR抑制剂（雷帕霉素类似物和mTOR激酶抑制剂）尚未显示出明确的治疗窗口。本综述的目的是介绍针对Ph样B-ALL治疗的新策略。我们讨论了在B-ALL中靶向mTOR的新方法，这些方法有可能克服先前mTOR抑制剂类别的局限性。一种方法是应用对mTOR复合物1（mTORC1）具有选择性的第三代双位抑制剂，并通过间歇给药显示出临床前疗效。一种独特的非药物方法是使用营养限制来靶向恶性B-ALL细胞中的信号传导和代谢依赖性。这两种新方法可以增强TKI在Ph样白血病中的疗效并提高生存率。
