Sekiya Sho, Fukuda Junki, Yamamura Ryodai, Ooshio Takako, Satoh Yusuke, Kosuge Shinya, Sato Reo, Hatanaka Kanako C, Hatanaka Yutaka, Mitsuhashi Tomoko, Nakamura Toru, Matsuno Yoshihiro, Hirano Satoshi, Sonoshita Masahiro
Division of Biomedical Oncology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan.
Department of Gastroenterological Surgery II, Hokkaido University Faculty of Medicine, Sapporo, Japan.
Cancer Res. 2023 Aug 15;83(16):2704-2715. doi: 10.1158/0008-5472.CAN-22-3762.
Significant progress has been made in understanding the pathogenesis of pancreatic ductal adenocarcinoma (PDAC) by generating and using murine models. To accelerate drug discovery by identifying novel therapeutic targets on a systemic level, here we generated a Drosophila model mimicking the genetic signature in PDAC (KRAS, TP53, CDKN2A, and SMAD4 alterations), which is associated with the worst prognosis in patients. The '4-hit' flies displayed epithelial transformation and decreased survival. Comprehensive genetic screening of their entire kinome revealed kinases including MEK and AURKB as therapeutic targets. Consistently, a combination of the MEK inhibitor trametinib and the AURKB inhibitor BI-831266 suppressed the growth of human PDAC xenografts in mice. In patients with PDAC, the activity of AURKB was associated with poor prognosis. This fly-based platform provides an efficient whole-body approach that complements current methods for identifying therapeutic targets in PDAC.
Development of a Drosophila model mimicking genetic alterations in human pancreatic ductal adenocarcinoma provides a tool for genetic screening that identifies MEK and AURKB inhibition as a potential treatment strategy.
通过构建和使用小鼠模型，在理解胰腺导管腺癌（PDAC）的发病机制方面取得了重大进展。为了通过在系统水平上识别新的治疗靶点来加速药物发现，我们在此构建了一种果蝇模型，该模型模拟了PDAC中的基因特征（KRAS、TP53、CDKN2A和SMAD4改变），这与患者的最差预后相关。“四重打击”果蝇表现出上皮转化和存活率降低。对其整个激酶组进行全面的基因筛选，发现包括MEK和AURKB在内的激酶为治疗靶点。一致地，MEK抑制剂曲美替尼和AURKB抑制剂BI-831266的组合抑制了小鼠体内人PDAC异种移植瘤的生长。在PDAC患者中，AURKB的活性与预后不良相关。这个基于果蝇的平台提供了一种有效的全身方法，可补充当前在PDAC中识别治疗靶点的方法。
构建模拟人类胰腺导管腺癌基因改变的果蝇模型，为基因筛选提供了一种工具，该筛选将MEK和AURKB抑制确定为一种潜在的治疗策略。
