RNF43 G659fs is an oncogenic colorectal cancer mutation and sensitizes tumor cells to PI3K/mTOR inhibition.
RNF43 G659fs is an oncogenic colorectal cancer mutation and sensitizes tumor cells to PI3K/mTOR inhibition.
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DOI：
10.1038/s41467-022-30794-7
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发表时间：
2022-06-08
影响因子：
16.6
通讯作者：
Giannakis, Marios
中科院分区：
文献类型：
--
作者：
Fang, Lishan;Ford-Roshon, Dane;Russo, Max;O'Brien, Casey;Xiong, Xiaozhe;Gurjao, Carino;Grandclaudon, Maximilien;Raghavan, Srivatsan;Corsello, Steven M.;Carr, Steven A.;Udeshi, Namrata D.;Berstler, James;Sicinska, Ewa;Ng, Kimmie;Giannakis, Marios
RNF43_p。G659fs突变在结直肠癌中经常发生，但其功能仍然知之甚少，并且没有针对这种改变的特异性治疗方法。在本研究中，我们发现RNF43_p。G659fs独立于Wnt信号促进细胞生长。我们进行药物再利用文库筛选，发现具有RNF43_p的细胞。G659突变可通过抑制PI3K信号传导而被选择性地杀死。PI3K/mTOR抑制剂在RNF43659mut等基因细胞系和异种移植模型中，以及在含有RNF43_p的患者来源的类器官中显示出有希望的抗肿瘤活性。G659fs突变。我们发现RNF43659mut结合p85，通过p85泛素化和降解导致PI3K信号通路增加。此外，RNF43659mut等基因细胞的rna测序显示，干扰素应答基因表达降低，而PI3K/mTOR抑制可逆转这一现象，表明RNF43659mut可能改变肿瘤免疫。我们的研究结果提示PI3K/mTOR抑制剂在治疗RNF43_p中的治疗应用。G659fs突变型癌症。RNF43 G659fs突变在结直肠癌中经常发生，但其功能尚不清楚。在这项研究中，作者发现RNF43 G659fs是一种致癌的结直肠癌突变，并使肿瘤细胞对PI3K/mTOR抑制敏感。
The RNF43_p.G659fs mutation occurs frequently in colorectal cancer, but its function remains poorly understood and there are no specific therapies directed against this alteration. In this study, we find that RNF43_p.G659fs promotes cell growth independent of Wnt signaling. We perform a drug repurposing library screen and discover that cells with RNF43_p.G659 mutations are selectively killed by inhibition of PI3K signaling. PI3K/mTOR inhibitors yield promising antitumor activity in RNF43659mut isogenic cell lines and xenograft models, as well as in patient-derived organoids harboring RNF43_p.G659fs mutations. We find that RNF43659mut binds p85 leading to increased PI3K signaling through p85 ubiquitination and degradation. Additionally, RNA-sequencing of RNF43659mut isogenic cells reveals decreased interferon response gene expression, that is reversed by PI3K/mTOR inhibition, suggesting that RNF43659mut may alter tumor immunity. Our findings suggest a therapeutic application for PI3K/mTOR inhibitors in treating RNF43_p.G659fs mutant cancers. The RNF43 G659fs mutation occurs frequently in colorectal cancer, but its function remains poorly understood. In this study, the authors show that RNF43 G659fs is an oncogenic colorectal cancer mutation and sensitizes tumor cells to PI3K/mTOR inhibition.
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DOI：
10.15252/embj.2019103932
发表时间：
2020-09-15
期刊：
The EMBO journal
影响因子：
--
作者：
Spit M;Fenderico N;Jordens I;Radaszkiewicz T;Lindeboom RG;Bugter JM;Cristobal A;Ootes L;van Osch M;Janssen E;Boonekamp KE;Hanakova K;Potesil D;Zdrahal Z;Boj SF;Medema JP;Bryja V;Koo BK;Vermeulen M;Maurice MM
通讯作者：
Maurice MM
影响因子：
5.2
作者：
Inamura K
通讯作者：
Inamura K
关于癌症基因组地图集的泛伴奏蛋白质组学观点。
影响因子：
16.6
作者：
Akbani, Rehan;Ng, Patrick Kwok Shing;Werner, Henrica M. J.;Shahmoradgoli, Maria;Zhang, Fan;Ju, Zhenlin;Liu, Wenbin;Yang, Ji-Yeon;Yoshihara, Kosuke;Li, Jun;Ling, Shiyun;Seviour, Elena G.;Ram, Prahlad T.;Minna, John D.;Diao, Lixia;Tong, Pan;Heymach, John V.;Hill, Steven M.;Dondelinger, Frank;Stadler, Nicolas;Byers, Lauren A.;Meric-Bernstam, Funda;Weinstein, John N.;Broom, Bradley M.;Verhaak, Roeland G. W.;Liang, Han;Mukherjee, Sach;Lu, Yiling;Mills, Gordon B.
通讯作者：
Mills, Gordon B.
影响因子：
64.8
作者：
Hao, Huai-Xiang;Xie, Yang;Cong, Feng
通讯作者：
Cong, Feng
影响因子：
64.8
作者：
Koo, Bon-Kyoung;Spit, Maureen;Clevers, Hans
通讯作者：
Clevers, Hans