Defining the therapeutic selective dependencies for distinct subtypes of PI3K pathway-altered prostate cancers.
Defining the therapeutic selective dependencies for distinct subtypes of PI3K pathway-altered prostate cancers.
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定义PI3K通路改变的前列腺癌的不同亚型的治疗选择性依赖性。
DOI：
10.1038/s41467-021-25341-9
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发表时间：
2021-08-20
影响因子：
16.6
通讯作者：
Carver BS
中科院分区：
文献类型：
--
作者：
Mao N;Zhang Z;Lee YS;Choi D;Rivera AA;Li D;Lee C;Haywood S;Chen X;Chang Q;Xu G;Chen HA;de Stanchina E;Sawyers C;Rosen N;Hsieh AC;Chen Y;Carver BS
以往的研究表明，PTEN缺失与p110β信号依赖有关，从而导致了p110β选择性抑制剂的临床发展。在这里，我们使用一组临床前模型来揭示PI3K亚型依赖不是由PTEN的丢失控制的，而是受到反馈抑制和同时发生的PIK3CA/PIK3CB改变的影响。此外，尽管在PTEN缺陷的肿瘤中抑制PAN-PI3K是有效的，但上调胰岛素样生长因子1受体(IGF1R)会促进耐药性。重要的是，我们发现这种耐药性可以通过靶向AKT来克服，我们发现在PTEN丢失的情况下，AKT抑制剂优于PAN-PI3K抑制。然而，在存在野生型PTEN和PIK3CA激活突变的情况下，p110α依赖的信号转导占主导地位，选择性地抑制p110α在治疗上优于对AKT的抑制。这些发现揭示了对PI3K异构体依赖性的更细微的理解，并揭示了以上下文特定的方式选择性地针对PI3K信号节点的新策略。了解前列腺癌中PI3K亚型依赖的机制有助于设计未来的临床试验。在这里，作者表明，PIK3CA或PIK3CB的功能增益突变可以赋予PI3K p110异构体依赖性，在PTEN缺失的前列腺癌中，AKT的直接抑制可能优于PI3K抑制。
Previous studies have suggested that PTEN loss is associated with p110β signaling dependency, leading to the clinical development of p110β-selective inhibitors. Here we use a panel pre-clinical models to reveal that PI3K isoform dependency is not governed by loss of PTEN and is impacted by feedback inhibition and concurrent PIK3CA/PIK3CB alterations. Furthermore, while pan-PI3K inhibition in PTEN-deficient tumors is efficacious, upregulation of Insulin Like Growth Factor 1 Receptor (IGF1R) promotes resistance. Importantly, we show that this resistance can be overcome through targeting AKT and we find that AKT inhibitors are superior to pan-PI3K inhibition in the context of PTEN loss. However, in the presence of wild-type PTEN and PIK3CA-activating mutations, p110α-dependent signaling is dominant and selectively inhibiting p110α is therapeutically superior to AKT inhibition. These discoveries reveal a more nuanced understanding of PI3K isoform dependency and unveil novel strategies to selectively target PI3K signaling nodes in a context-specific manner. Understanding the mechanisms driving PI3K isoform dependency in prostate cancer can help the design of future clinical trials. Here, the authors show that gain-of-function mutations in PIK3CA or PIK3CB can confer PI3K p110 isoform dependency and that the direct inhibition of AKT may be superior to PI3K inhibition in PTEN-deficient prostate cancers.
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DOI：
10.1186/s13058-016-0697-1
发表时间：
2016-04-05
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Leroy C;Ramos P;Cornille K;Bonenfant D;Fritsch C;Voshol H;Bentires-Alj M
通讯作者：
Bentires-Alj M
影响因子：
64.5
作者：
Karthaus WR;Iaquinta PJ;Drost J;Gracanin A;van Boxtel R;Wongvipat J;Dowling CM;Gao D;Begthel H;Sachs N;Vries RGJ;Cuppen E;Chen Y;Sawyers CL;Clevers HC
通讯作者：
Clevers HC
影响因子：
64.5
作者：
Gao D;Vela I;Sboner A;Iaquinta PJ;Karthaus WR;Gopalan A;Dowling C;Wanjala JN;Undvall EA;Arora VK;Wongvipat J;Kossai M;Ramazanoglu S;Barboza LP;Di W;Cao Z;Zhang QF;Sirota I;Ran L;MacDonald TY;Beltran H;Mosquera JM;Touijer KA;Scardino PT;Laudone VP;Curtis KR;Rathkopf DE;Morris MJ;Danila DC;Slovin SF;Solomon SB;Eastham JA;Chi P;Carver B;Rubin MA;Scher HI;Clevers H;Sawyers CL;Chen Y
通讯作者：
Chen Y
影响因子：
8.8
作者：
Heudel PE;Fabbro M;Roemer-Becuwe C;Kaminsky MC;Arnaud A;Joly F;Roche-Forestier S;Meunier J;Foa C;You B;Priou F;Tazi Y;Floquet A;Selle F;Berton-Rigaud D;Lesoin A;Kalbacher E;Lortholary A;Favier L;Treilleux I;Ray-Coquard I
通讯作者：
Ray-Coquard I
影响因子：
7.5
作者：
Jia S;Roberts TM;Zhao JJ
通讯作者：
Zhao JJ