Ecole Polytechnique Fédérale de Lausanne, School of Life Sciences, Swiss Institute for Experimental Cancer Research, Swiss Cancer Center Leman, Lausanne, Switzerland.
Translational Data Science, Swiss Institute of Bioinformatics, AGORA Cancer Research Center, Lausanne, Switzerland.
Blood Adv. 2023 Oct 24;7(20):6240-6252. doi: 10.1182/bloodadvances.2023010380.
Gain-of-function mutations in NOTCH1 are among the most frequent genetic alterations in T-cell acute lymphoblastic leukemia (T-ALL), highlighting the Notch signaling pathway as a promising therapeutic target for personalized medicine. Yet, a major limitation for long-term success of targeted therapy is relapse due to tumor heterogeneity or acquired resistance. Thus, we performed a genome-wide CRISPR-Cas9 screen to identify prospective resistance mechanisms to pharmacological NOTCH inhibitors and novel targeted combination therapies to efficiently combat T-ALL. Mutational loss of phosphoinositide-3-kinase regulatory subunit 1 (PIK3R1) causes resistance to Notch inhibition. PIK3R1 deficiency leads to increased PI3K/AKT signaling, which regulates cell cycle and the spliceosome machinery, both at the transcriptional and posttranslational level. Moreover, several therapeutic combinations have been identified, in which simultaneous targeting of the cyclin-dependent kinases 4 and 6 (CDK4/6) and NOTCH proved to be the most efficacious in T-ALL xenotransplantation models.
NOTCH1 基因功能获得性突变是 T 细胞急性淋巴细胞白血病（T-ALL）中最常见的遗传改变之一，这突显了 Notch 信号通路作为个性化医学有前途的治疗靶点。然而，靶向治疗长期成功的主要限制是由于肿瘤异质性或获得性耐药而导致的复发。因此，我们进行了全基因组 CRISPR-Cas9 筛选，以确定对药理学 NOTCH 抑制剂和新型靶向联合治疗的潜在耐药机制，从而有效地治疗 T-ALL。磷酸肌醇-3-激酶调节亚基 1（PIK3R1）的突变缺失导致对 Notch 抑制的耐药性。PIK3R1 缺陷导致 PI3K/AKT 信号转导增加，该信号转导在转录和翻译后水平上调节细胞周期和剪接体机制。此外，已经确定了几种治疗组合，其中同时靶向细胞周期蛋白依赖性激酶 4 和 6（CDK4/6）和 NOTCH 在 T-ALL 异种移植模型中被证明是最有效的。
Zotero 插件
