Targeting wild-type KRAS-amplified gastroesophageal cancer through combined MEK and SHP2 inhibition.
Targeting wild-type KRAS-amplified gastroesophageal cancer through combined MEK and SHP2 inhibition.
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DOI：
10.1038/s41591-018-0022-x
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发表时间：
2018-07
期刊：
影响因子：
82.9
通讯作者：
Bass AJ
中科院分区：
文献类型：
--
作者：
Wong GS;Zhou J;Liu JB;Wu Z;Xu X;Li T;Xu D;Schumacher SE;Puschhof J;McFarland J;Zou C;Dulak A;Henderson L;Xu P;O'Day E;Rendak R;Liao WL;Cecchi F;Hembrough T;Schwartz S;Szeto C;Rustgi AK;Wong KK;Diehl JA;Jensen K;Graziano F;Ruzzo A;Fereshetian S;Mertins P;Carr SA;Beroukhim R;Nakamura K;Oki E;Watanabe M;Baba H;Imamura Y;Catenacci D;Bass AJ
当通过典型突变激活时，KRAS 在癌症中的作用已得到充分证实。在这里，我们探索了癌症中 KRAS 激活的第二种方法，即在没有编码突变的情况下 KRAS 基因的局部高水平扩增。这些扩增最常见于食管、胃和卵巢腺癌。 KRAS 扩增的胃癌模型具有 KRAS 蛋白的显着过度表达，并且由于其能够通过快速增加 KRAS-GTP 水平做出适应性反应，因此对 MAPK 阻断不敏感。我们证明，抑制鸟嘌呤交换因子 SOS1/2 或蛋白酪氨酸磷酸酶 SHP2 可以减弱这种适应性过程，并且从遗传和药理学角度靶向这些因子可以增强 KRAS 扩增模型在体外和体内环境中对 MEK 抑制的敏感性。这些数据证明了拷贝数扩增作为 KRAS 激活机制的相关性，并揭示了通过组合 SHP2 和 MEK 抑制来靶向这些肿瘤的治疗潜力。
The role of KRAS, when activated through canonical mutations, has been well established in cancer. Here we explore a secondary means of KRAS activation in cancer, focal high-level amplification of the KRAS gene in the absence of coding mutations. These amplifications occur most commonly in esophageal, gastric and ovarian adenocarcinomas. KRAS amplified gastric cancer models possess marked overexpression of KRAS protein and are insensitive to MAPK blockade due to their capacity to adaptively respond by rapidly increasing KRAS-GTP levels. We demonstrate that inhibition of guanine exchange factors SOS1/2 or protein tyrosine phosphatase, SHP2, can attenuate this adaptive process and that targeting of these factors, both genetically and pharmacologically, can enhance sensitivity of KRAS-amplified models to MEK inhibition both in in vitro and in vivo settings. These data demonstrate the relevance of copy number amplification as a mechanism of KRAS activation, and uncover the therapeutic potential for targeting of these tumors through combined SHP2 and MEK inhibition.
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影响因子：
16.6
作者：
通讯作者：
--
影响因子：
64.5
作者：
Burgess MR;Hwang E;Mroue R;Bielski CM;Wandler AM;Huang BJ;Firestone AJ;Young A;Lacap JA;Crocker L;Asthana S;Davis EM;Xu J;Akagi K;Le Beau MM;Li Q;Haley B;Stokoe D;Sampath D;Taylor BS;Evangelista M;Shannon K
通讯作者：
Shannon K
影响因子：
3.7
作者：
Chen Y;McGee J;Chen X;Doman TN;Gong X;Zhang Y;Hamm N;Ma X;Higgs RE;Bhagwat SV;Buchanan S;Peng SB;Staschke KA;Yadav V;Yue Y;Kouros-Mehr H
通讯作者：
Kouros-Mehr H
影响因子：
4.8
作者：
Kamioka, Yuji;Yasuda, Shuhei;Matsuda, Michiyuki
通讯作者：
Matsuda, Michiyuki
影响因子：
7.3
作者：
Fortanet, Jorge Garcia;Chen, Christine Hiu-Tung;LaMarche, Matthew J.
通讯作者：
LaMarche, Matthew J.