美国俄勒冈健康与科学大学Elie Traer课题组在研究中取得进展。他们发现急性髓系白血病 (AML)  微环境催化对 gilteritinib 耐药的逐步演变。相关论文发表在2021年6月24日出版的《癌细胞》杂志上。

他们通过整合全外显子组测序、CRISPR-Cas9、代谢组学、蛋白质组学和药理学方法，从机制上定义了早期和晚期耐药性。早期耐药细胞经历代谢重编程，生长更慢，并且依赖于Aurora激酶 B (AURKB)。晚期抗性细胞的特征是预先存在的 NRAS 突变亚克隆的扩增和持续的代谢重编程。他们的模型密切反映了接受 gilteritinib 治疗的 AML 患者的时间和突变。 AURKB 的药理学抑制使来自 gilteritinib 治疗的 AML 患者的早期耐药细胞培养物和原代白血病细胞重新敏感。这些发现支持在预先存在的耐药突变发生扩大之前，用 AURKB 抑制剂和 gilteritinib 靶向早期耐药 AML 细胞的组合策略。

该研究详细介绍了 FLT3 突变的AML中gilteritinib 耐药性的逐步演变。早期耐药是由保护残留白血病细胞的骨髓微环境介导的。随着时间的推移，白血病细胞进化出内在的耐药机制或晚期耐药机制。

附：英文原文

Title: The AML microenvironment catalyzes a stepwise evolution to gilteritinib resistance

Author: Sunil K. Joshi, Tamilla Nechiporuk, Daniel Bottomly, Paul D. Piehowski, Julie A. Reisz, Janét Pittsenbarger, Andy Kaempf, Sara J.C. Gosline, Yi-Ting Wang, Joshua R. Hansen, Marina A. Gritsenko, Chelsea Hutchinson, Karl K. Weitz, Jamie Moon, Francesca Cendali, Thomas L. Fillmore, Chia-Feng Tsai, Athena A. Schepmoes, Tujin Shi, Osama A. Arshad, Jason E. McDermott, Ozgun Babur, Kevin Watanabe-Smith, Emek Demir, Angelo DAlessandro, Tao Liu, Cristina E. Tognon, Jeffrey W. Tyner, Shannon K. McWeeney, Karin D. Rodland, Brian J. Druker, Elie Traer

Issue&Volume: 2021-06-24

Abstract: Our study details the stepwise evolution of gilteritinib resistance in FLT3-mutated acute myeloid leukemia (AML). Early resistance is mediated by the bone marrowmicroenvironment, which protects residual leukemia cells. Over time, leukemia cellsevolve intrinsic mechanisms of resistance, or late resistance. We mechanisticallydefine both early and late resistance by integrating whole-exome sequencing, CRISPR-Cas9,metabolomics, proteomics, and pharmacologic approaches. Early resistant cells undergometabolic reprogramming, grow more slowly, and are dependent upon Aurora kinase B(AURKB). Late resistant cells are characterized by expansion of pre-existing NRAS mutant subclones and continued metabolic reprogramming. Our model closely mirrorsthe timing and mutations of AML patients treated with gilteritinib. Pharmacologicalinhibition of AURKB resensitizes both early resistant cell cultures and primary leukemiacells from gilteritinib-treated AML patients. These findings support a combinatorialstrategy to target early resistant AML cells with AURKB inhibitors and gilteritinibbefore the expansion of pre-existing resistance mutations occurs.

DOI: 10.1016/j.ccell.2021.06.003

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(21)00286-5