Princess Maxima Center for Pediatric Oncology, Utrecht, The Netherlands.
Laboratory of Pediatric Oncology, Department of Pediatrics, and.
Blood. 2021 Dec 9;138(23):2383-2395. doi: 10.1182/blood.2021011787.
Asparaginase (ASNase) therapy has been a mainstay of acute lymphoblastic leukemia (ALL) protocols for decades and shows promise in the treatment of a variety of other cancers. To improve the efficacy of ASNase treatment, we used a CRISPR/Cas9-based screen to identify actionable signaling intermediates that improve the response to ASNase. Both genetic inactivation of Bruton's tyrosine kinase (BTK) and pharmacological inhibition by the BTK inhibitor ibrutinib strongly synergize with ASNase by inhibiting the amino acid response pathway, a mechanism involving c-Myc-mediated suppression of GCN2 activity. This synthetic lethal interaction was observed in 90% of patient-derived xenografts, regardless of the genomic subtype. Moreover, ibrutinib substantially improved ASNase treatment response in a murine PDX model. Hence, ibrutinib may be used to enhance the clinical efficacy of ASNase in ALL. This trial was registered at www.clinicaltrials.gov as # NCT02884453.
天冬酰胺酶（ASNase）治疗已成为急性淋巴细胞白血病（ALL）方案的主要方法，并在治疗多种其他癌症方面显示出前景。为了提高 ASNase 治疗的疗效，我们使用基于 CRISPR/Cas9 的筛选来鉴定可改善 ASNase 反应的可行信号中间体。布鲁顿酪氨酸激酶（BTK）的基因失活和 BTK 抑制剂伊布替尼的药理抑制均通过抑制氨基酸反应途径强烈协同作用于 ASNase，该机制涉及 c-Myc 介导的 GCN2 活性抑制。这种合成致死性相互作用在 90%的患者来源的异种移植中观察到，与基因组亚型无关。此外，伊布替尼在小鼠 PDX 模型中显著改善了 ASNase 治疗的反应。因此，伊布替尼可用于提高 ALL 中 ASNase 的临床疗效。该试验在 www.clinicaltrials.gov 上注册为 #NCT02884453。
