The novel driver gene ASAP2 is a potential druggable target in pancreatic cancer.
The novel driver gene ASAP2 is a potential druggable target in pancreatic cancer.
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DOI：
10.1111/cas.14858
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发表时间：
2021-04
期刊：
影响因子：
5.7
通讯作者：
Mimori K
中科院分区：
文献类型：
--
作者：
Fujii A;Masuda T;Iwata M;Tobo T;Wakiyama H;Koike K;Kosai K;Nakano T;Kuramitsu S;Kitagawa A;Sato K;Kouyama Y;Shimizu D;Matsumoto Y;Utsunomiya T;Ohtsuka T;Yamanishi Y;Nakamura M;Mimori K
靶向突变癌基因是治疗癌症的有效途径。胰腺导管腺癌（pancreatic ductal adencarcinoma， PDAC）的4个主要驱动基因是KRAS、TP53、CDKN2A和SMAD4，它们被统称为PDAC的“四大基因”，但它们仍然是具有挑战性的治疗靶点。在本研究中，ArfGAP家族成员之一的具有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的一个新的驱动基因。PDAC数据集的临床分析显示，基于DNA拷贝数的增加，ASAP2在PDAC细胞中过表达，ASAP2的高表达导致PDAC预后不良。使用CRISPR - Cas9技术产生的ASAP2敲除PDAC细胞或转染的PDAC细胞来研究ASAP2的生物学作用。体外和体内分析表明，ASAP2通过磷酸化表皮生长因子受体（EGFR）促进细胞周期进程，从而促进肿瘤生长。利用生物信息学方法确定了一种靶向ASAP2通路的重新定位药物。基因扰动相关法显示，抗寄生虫药物氯硝柳胺通过抑制ASAP2的表达抑制PDAC的生长。这些数据表明ASAP2是一种新的可药物驱动基因，可以激活EGFR信号通路。此外，氯硝柳胺被确定为PDAC的重新定位治疗剂，可能靶向ASAP2。在本研究中，我们通过生物信息学分析，确定了具有SH3结构域、锚蛋白重复序列和PH结构域2 （ASAP2）的ArfGAP在世界上最致命的癌症之一胰腺导管腺癌（PDAC）中是一个潜在的可药物驱动基因。然后，我们发现ASAP2通过磷酸化EGFR促进细胞周期进程，从而促进细胞迁移和增殖。最后，我们确定了抗寄生虫药物氯硝柳胺作为PDAC的重新定位治疗剂，可能靶向ASAP2。
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. In this study, we identified ArfGAP with SH3 domain, ankyrin repeat and PH domain 2 (ASAP2) as a potentially druggable driver gene using bioinformatics analysis in pancreatic ductal adenocarcinoma (PDAC), which is one of the most lethal cancers worldwide. Then, we showed that ASAP2 promoted cell migration and proliferation by facilitating cell cycle progression through phosphorylation of EGFR. Finally, we identified niclosamide, an antiparasitic drug, as a repositioned therapeutic agent for PDAC, possibly targeting ASAP2.
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影响因子：
64.5
作者：
Davoli T;Xu AW;Mengwasser KE;Sack LM;Yoon JC;Park PJ;Elledge SJ
通讯作者：
Elledge SJ
影响因子：
64.8
作者：
Notta F;Chan-Seng-Yue M;Lemire M;Li Y;Wilson GW;Connor AA;Denroche RE;Liang SB;Brown AM;Kim JC;Wang T;Simpson JT;Beck T;Borgida A;Buchner N;Chadwick D;Hafezi-Bakhtiari S;Dick JE;Heisler L;Hollingsworth MA;Ibrahimov E;Jang GH;Johns J;Jorgensen LG;Law C;Ludkovski O;Lungu I;Ng K;Pasternack D;Petersen GM;Shlush LI;Timms L;Tsao MS;Wilson JM;Yung CK;Zogopoulos G;Bartlett JM;Alexandrov LB;Real FX;Cleary SP;Roehrl MH;McPherson JD;Stein LD;Hudson TJ;Campbell PJ;Gallinger S
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Gallinger S
影响因子：
64.8
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影响因子：
29.4
作者：
Kanda M;Matthaei H;Wu J;Hong SM;Yu J;Borges M;Hruban RH;Maitra A;Kinzler K;Vogelstein B;Goggins M
通讯作者：
Goggins M
影响因子：
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Qian ZR;Rubinson DA;Nowak JA;Morales-Oyarvide V;Dunne RF;Kozak MM;Welch MW;Brais LK;Da Silva A;Li T;Li W;Masuda A;Yang J;Shi Y;Gu M;Masugi Y;Bui J;Zellers CL;Yuan C;Babic A;Khalaf N;Aguirre A;Ng K;Miksad RA;Bullock AJ;Chang DT;Tseng JF;Clancy TE;Linehan DC;Findeis-Hosey JJ;Doyle LA;Thorner AR;Ducar M;Wollison B;Laing A;Hahn WC;Meyerson M;Fuchs CS;Ogino S;Hornick JL;Hezel AF;Koong AC;Wolpin BM
通讯作者：
Wolpin BM