Incomplete inhibition of phosphorylation of 4E-BP1 as a mechanism of primary resistance to ATP-competitive mTOR inhibitors.
Incomplete inhibition of phosphorylation of 4E-BP1 as a mechanism of primary resistance to ATP-competitive mTOR inhibitors.
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作者：
哺乳动物雷帕霉素靶蛋白（mTOR）通过整合营养和生长因子信号调节细胞生长，并与癌症密切相关。但mTOR不是致癌基因，目前尚不清楚哪些肿瘤对新的ATP竞争性mTOR抑制剂具有耐药性或敏感性。我们筛选了一组超过600种人类癌细胞系，以鉴定对mTOR抑制剂PP 242的抗性和敏感性的标志物。RAS和PIK 3CA突变分别是对PP 242耐药和敏感性的最显著遗传标记;结肠来源是基于组织类型的耐药的最显著标记。在结肠癌细胞系中，具有KRAS突变的细胞系对PP 242最耐药，而没有KRAS突变的细胞系对PP 242最敏感。令人惊讶的是，具有PIK 3CA和KRAS共突变的细胞系具有中等敏感性。对mTOR下游信号传导靶点的免疫印迹分析显示，PP 242诱导的细胞生长抑制程度与翻译阻遏物4 E-BP 1的磷酸化抑制相关，但与核糖体蛋白S6无关。在患者来源的结肠癌异种移植物中的PP 242的肿瘤生长抑制试验中，与KRAS WT对照相比，在没有PIK 3CA共突变的KRAS突变体肿瘤中再次观察到对PP 242诱导的4 E-BP 1磷酸化和异种移植物生长的抑制的抗性。我们发现，在没有PIK 3CA共突变的情况下，KRAS突变与对PP 242的抗性相关，并且这与4 E-BP 1磷酸化水平的变化特别相关。
The mammalian target of rapamycin (mTOR) regulates cell growth by integrating nutrient and growth factor signaling and is strongly implicated in cancer. But mTOR is not an oncogene, and which tumors will be resistant or sensitive to new ATP-competitive mTOR inhibitors now in clinical trials remains unknown. We screened a panel of over 600 human cancer cell lines to identify markers of resistance and sensitivity to the mTOR inhibitor PP242. RAS and PIK3CA mutations were the most significant genetic markers for resistance and sensitivity to PP242, respectively; colon origin was the most significant marker for resistance based on tissue type. Among colon cancer cell lines, those with KRAS mutations were most resistant to PP242, while those without KRAS mutations most sensitive. Surprisingly, cell lines with co-mutation of PIK3CA and KRAS had intermediate sensitivity. Immunoblot analysis of the signaling targets downstream of mTOR revealed that the degree of cellular growth inhibition induced by PP242 was correlated with inhibition of phosphorylation of the translational repressor 4E-BP1, but not ribosomal protein S6. In a tumor growth inhibition trial of PP242 in patient-derived colon cancer xenografts, resistance to PP242 induced inhibition of 4E-BP1 phosphorylation and xenograft growth was again observed in KRAS mutant tumors without PIK3CA co-mutation, compared to KRAS WT controls. We show that, in the absence of PIK3CA co-mutation, KRAS mutations are associated with resistance to PP242 and that this is specifically linked to changes in the level of phosphorylation of 4E-BP1.
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DOI：
10.1126/science.1226344
发表时间：
2012-10-12
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Iyer G;Hanrahan AJ;Milowsky MI;Al-Ahmadie H;Scott SN;Janakiraman M;Pirun M;Sander C;Socci ND;Ostrovnaya I;Viale A;Heguy A;Peng L;Chan TA;Bochner B;Bajorin DF;Berger MF;Taylor BS;Solit DB
通讯作者：
Solit DB
雷帕霉素在I期试验中针对复发性PTEN缺陷型胶质母细胞瘤患者的抗肿瘤活性。
影响因子：
15.8
作者：
Cloughesy, Tim F.;Yoshimoto, Koji;Nghiemphu, Phioanh;Brown, Kevin;Dang, Julie;Zhu, Shaojun;Hsueh, Teli;Chen, Yinan;Wang, Wei;Youngkin, David;Liau, Linda;Martin, Neil;Becker, Don;Bergsneider, Marvin;Lai, Albert;Green, Richard;Oglesby, Tom;Koleto, Michael;Trent, Jeff;Horvath, Steve;Mischel, Paul S.;Mellinghoff, Ingo K.;Sawyers, Charles L.
通讯作者：
Sawyers, Charles L.
影响因子：
11.2
作者：
Janku F;Wheler JJ;Naing A;Falchook GS;Hong DS;Stepanek VM;Fu S;Piha-Paul SA;Lee JJ;Luthra R;Tsimberidou AM;Kurzrock R
通讯作者：
Kurzrock R
影响因子：
56.9
作者：
Cohen, MS;Zhang, C;Taunton, J
通讯作者：
Taunton, J
DOI：
10.1073/pnas.1108237108
发表时间：
2011-09-13
影响因子：
11.1
作者：
Ilic, Nina;Utermark, Tamara;Roberts, Thomas M.
通讯作者：
Roberts, Thomas M.