Phosphatidylinositol 3-kinase hyperactivation results in lapatinib resistance that is reversed by the mTOR/phosphatidylinositol 3-kinase inhibitor NVP-BEZ235.
Phosphatidylinositol 3-kinase hyperactivation results in lapatinib resistance that is reversed by the mTOR/phosphatidylinositol 3-kinase inhibitor NVP-BEZ235.
复制标题
磷脂酰肌醇3-激酶过度激活导致拉帕替尼的抗性，这是由mTOR/磷脂酰/磷脂酰肌醇3-激酶抑制剂NVP-BEZ235逆转的。
DOI：
10.1158/0008-5472.can-08-1740
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发表时间：
2008-11-15
期刊：
影响因子：
11.2
通讯作者：
Baselga J
中科院分区：
文献类型：
--
作者：
Eichhorn PJ;Gili M;Scaltriti M;Serra V;Guzman M;Nijkamp W;Beijersbergen RL;Valero V;Seoane J;Bernards R;Baselga J
HER2小分子抑制剂在曲妥珠单抗治疗进展的晚期HER2阳性乳腺癌患者中具有临床活性。然而，这类药物的有效性受到原发耐药性或获得性耐药性的限制。使用无偏遗传方法，我们进行了全基因组功能缺失shRNA筛选，以鉴定对拉帕替尼（一种最近批准的抗her2酪氨酸激酶抑制剂）耐药的新调节剂。在这里，我们已经确定肿瘤抑制因子PTEN在体外和体内作为拉帕替尼敏感性的调节剂。此外，研究人员发现，在乳腺癌中普遍存在的PIK3CA的两个显性激活突变（E545K和H1047R）也赋予了对拉帕替尼的耐药性。此外，我们发现PI3K诱导的拉帕替尼耐药可以通过使用NVP-BEZ235 （PI3K/mTOR的双重抑制剂）来消除。我们的数据显示，通过PTEN的功能丧失突变或PIK3CA的显性激活突变，PI3K通路的失调会导致拉帕替尼耐药，而NVP-BEZ235可以有效逆转这种耐药。
Small molecule inhibitors of HER2 are clinically active in women with advanced HER2 positive breast cancer who have progressed on trastuzumab treatment. However, the effectiveness of this class of agents is limited by either primary resistance or acquired resistance. Using an unbiased genetic approach we performed a genome wide loss-of-function shRNA screen to identify novel modulators of resistance to lapatinib, a recently approved anti-HER2 tyrosine kinase inhibitor. Here, we have identified the tumour suppressor PTEN as a modulator of lapatinib sensitivity in vitro and in vivo. In addition, we demonstrate that two dominant activating mutations in PIK3CA (E545K and H1047R), which are prevalent in breast cancer, also confer resistance to lapatinib. Furthermore, we show that PI3K induced lapatinib resistance can be abrogated through the use of NVP-BEZ235, a dual inhibitor of PI3K/mTOR. Our data show that deregulation of the PI3K pathway, either through loss-of-function mutations in PTEN or dominant activating mutations in PIK3CA, leads to lapatinib resistance which can be effectively reversed by NVP-BEZ235.