新型驱动基因 ASAP2 是胰腺癌的潜在药物靶点,Cancer Science

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新型驱动基因 ASAP2 是胰腺癌的潜在药物靶点
Cancer Science ( IF 4.5 ) Pub Date : 2021-02-19 , DOI: 10.1111/cas.14858
Atsushi Fujii _{1,

2} , Takaaki Masuda ₁ , Michio Iwata ₃ , Taro Tobo ₄ , Hiroaki Wakiyama ₁ , Kensuke Koike ₁ , Keisuke Kosai ₁ , Takafumi Nakano ₁ , Shotaro Kuramitsu ₁ , Akihiro Kitagawa ₁ , Kuniaki Sato ₁ , Yuta Kouyama ₁ , Dai Shimizu ₁ , Yoshihiro Matsumoto ₁ , Tohru Utsunomiya ₅ , Takao Ohtsuka ₆ , Yoshihiro Yamanishi ₃ , Masafumi Nakamura ₂ , Koshi Mimori ₁

Affiliation

针对突变癌基因是治疗癌症的有效方法。胰腺导管腺癌 (PDAC) 的 4 个主要驱动基因是KRAS、TP53、CDKN2A和SMAD4，统称为 PDAC 的“四大”，但它们仍然是具有挑战性的治疗靶点。在本研究中， ArfGAP 家族之一的具有 SH3 结构域、锚蛋白重复序列和 PH 结构域 2 ( ASAP2 ) 的 ArfGAP 被确定为 PDAC 中的新型驱动基因。PDAC 数据集的临床分析表明，由于 DNA 拷贝数增加，ASAP2在 PDAC 细胞中过度表达，并且ASAP2高表达导致 PDAC 预后不良。使用通过 CRISPR-Cas9 技术产生的ASAP2敲除 PDAC 细胞或转染的 PDAC 细胞研究了ASAP2的生物学作用。体外和体内分析表明，ASAP2 通过表皮生长因子受体 (EGFR) 的磷酸化促进细胞周期进程，从而促进肿瘤生长。使用生物信息学方法鉴定了针对 ASAP2 途径的重新定位药物。基因扰动相关方法表明，抗寄生虫药氯硝柳胺通过抑制 ASAP2 表达来抑制 PDAC 生长。这些数据表明ASAP2是一种新型药物驱动基因，可激活 EGFR 信号通路。此外，氯硝柳胺被确定为可能针对 ASAP2 的 PDAC 重新定位治疗剂。

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The novel driver gene ASAP2 is a potential druggable target in pancreatic cancer

Targeting mutated oncogenes is an effective approach for treating cancer. The 4 main driver genes of pancreatic ductal adenocarcinoma (PDAC) are KRAS, TP53, CDKN2A, and SMAD4, collectively called the “big 4” of PDAC, however they remain challenging therapeutic targets. In this study, ArfGAP with SH3 domain, ankyrin repeat and PH domain 2 (ASAP2), one of the ArfGAP family, was identified as a novel driver gene in PDAC. Clinical analysis with PDAC datasets showed that ASAP2 was overexpressed in PDAC cells based on increased DNA copy numbers, and high ASAP2 expression contributed to a poor prognosis in PDAC. The biological roles of ASAP2 were investigated using ASAP2‐knockout PDAC cells generated with CRISPR‐Cas9 technology or transfected PDAC cells. In vitro and in vivo analyses showed that ASAP2 promoted tumor growth by facilitating cell cycle progression through phosphorylation of epidermal growth factor receptor (EGFR). A repositioned drug targeting the ASAP2 pathway was identified using a bioinformatics approach. The gene perturbation correlation method showed that niclosamide, an antiparasitic drug, suppressed PDAC growth by inhibition of ASAP2 expression. These data show that ASAP2 is a novel druggable driver gene that activates the EGFR signaling pathway. Furthermore, niclosamide was identified as a repositioned therapeutic agent for PDAC possibly targeting ASAP2.

更新日期：2021-04-04

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