致癌性IDH突变的非竞争性抑制的失效可导致获得性耐药

2023-01-24 09:36

全面扫描碱基编辑的白血病细胞中的IDH单氨基酸变体，发现通过使NADPH依赖的非竞争性抑制失效而对IDH抑制产生抗性的复发突变。

SCI 20 January 2022

Disabling Uncompetitive Inhibition of Oncogenic IDH Mutations Drives Acquired Resistance

(Cancer Discov, IF: 38.272)

Lyu Junhua,Liu Yuxuan,Gong Lihu et al. Disabling Uncompetitive Inhibition of Oncogenic IDH Mutations Drives Acquired Resistance.[J] .Cancer Discov, 2023, 13: 170-193.

Abstract 摘要

Mutations in IDH genes occur frequently in acute myeloid leukemia (AML) and other human cancers to generate the oncometabolite R-2HG. Allosteric inhibition of mutant IDH suppresses R-2HG production in a subset of patients with AML; however, acquired resistance emerges as a new challenge, and the underlying mechanisms remain incompletely understood. Here we establish isogenic leukemia cells containing common IDH oncogenic mutations by CRISPR base editing. By mutational scanning of IDH single amino acid variants in base-edited cells, we describe a repertoire of IDH second-site mutations responsible for therapy resistance through disabling uncompetitive enzyme inhibition. Recurrent mutations at NADPH binding sites within IDH heterodimers act in cis or trans to prevent the formation of stable enzyme-inhibitor complexes, restore R-2HG production in the presence of inhibitors, and drive therapy resistance in IDH-mutant AML cells and patients. We therefore uncover a new class of pathogenic mutations and mechanisms for acquired resistance to targeted cancer therapies.

IDH基因突变经常发生在急性髓系白血病(AML)和其他人类癌症中，以产生肿瘤代谢产物R-2HG。空间异构抑制的突变IDH阻碍了AML患者R-2HG的产生。然而，获得性耐药成为一项新的挑战，其潜在机制仍未完全了解。在这里，我们通过CRISPR碱基编辑建立了包含常见IDH癌基因突变的等基因白血病细胞。通过对碱基编辑细胞中IDH单氨基酸变异的突变扫描，我们描述了IDH第二位点突变的一系列序列，这些突变通过使非竞争性酶抑制失效而导致治疗耐药性。IDH异二聚体内NADPH结合位点的反复突变以顺式或反式方式作用，以防止稳定酶抑制剂复合物的形成，在抑制剂存在的情况下恢复R-2HG的产生，并驱动IDH突变AML细胞和患者的治疗耐药性。因此，我们发现了一类新的致病性突变和获得性抵抗靶向癌症治疗的机制。

SIGNIFICANCE 意义

Comprehensive scanning of IDH single amino acid variants in base-edited leukemia cells uncovers recurrent mutations conferring resistance to IDH inhibition through disabling NADPH-dependent uncompetitiveinhibition. Together with targeted sequencing, structural, and functional studies, we identify a new class of pathogenic mutations and mechanisms for acquired resistance to IDH-targeting cancer therapies.

全面扫描碱基编辑的白血病细胞中的IDH单氨基酸变体，发现通过使NADPH依赖的非竞争性抑制失效而对IDH抑制产生抗性的复发突变。结合靶向测序、结构和功能研究，我们发现了一类新的致病突变和IDH靶向癌症治疗的获得性耐药机制。