Sensitizing Triple-Negative Breast Cancer to PI3K Inhibition by Cotargeting IGF1R
Sensitizing Triple-Negative Breast Cancer to PI3K Inhibition by Cotargeting IGF1R
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DOI：
10.1158/1535-7163.mct-15-0865
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发表时间：
2016-07-01
影响因子：
5.7
通讯作者：
Beijersbergen, Roderick L.
中科院分区：
文献类型：
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作者：
de Lint, Klaas;Poell, Jos B.;Beijersbergen, Roderick L.
靶向治疗已被证明在乳腺癌的治疗中是非常宝贵的，例如他莫昔芬治疗激素受体阳性肿瘤和曲妥珠单抗治疗HER2阳性肿瘤。相比之下，这些标志物阴性的乳腺癌亚组，三阴性乳腺癌（TNBC），在通路靶向治疗方面取得了有限的成功。大部分TNBC的增殖和存活依赖于PI3K途径，但单独抑制PI3K通常具有有限的临床益处。我们在人TNBC细胞系中进行了基于RNAi的遗传筛选，以鉴定其敲低与PI3K抑制剂GDC-0941（pictilisib）协同作用的激酶。我们发现，胰岛素样生长因子-1受体（IGF1R）表达的敲低有效地增加了这些细胞对GDC-0941的敏感性。使用OSI-906（linsitinib）对IGF1R的药理学抑制显示出与PI3K抑制的强协同作用。此外，我们发现GDC-0941和OSI-906的组合在来自一组18个TNBC细胞系的8个系中是协同的。在这些细胞系中，当PI3K被抑制时，IGF1R的抑制进一步降低下游PI3K通路组分的活性。TNBC细胞系组的表达分析表明，IGF2BP3的表达水平可用作对PI3K/IGF1R抑制剂组合的敏感性的潜在预测因子。我们的数据显示，PI3K和IGF1R抑制剂组成的联合治疗可能对TNBC亚组有益。(C)2016年AACR。
Targeted therapies have proven invaluable in the treatment of breast cancer, as exemplified by tamoxifen treatment for hormone receptor-positive tumors and trastuzumab treatment for HER2-positive tumors. In contrast, a subset of breast cancer negative for these markers, triple-negative breast cancer (TNBC), has met limited success with pathway-targeted therapies. A large fraction of TNBCs depend on the PI3K pathway for proliferation and survival, but inhibition of PI3K alone generally has limited clinical benefit. We performed an RNAi-based genetic screen in a human TNBC cell line to identify kinases whose knockdown synergizes with the PI3K inhibitor GDC-0941 (pictilisib). We discovered that knockdown of insulin-like growth factor-1 receptor (IGF1R) expression potently increased sensitivity of these cells to GDC-0941. Pharmacologic inhibition of IGF1R using OSI-906 (linsitinib) showed a strong synergy with PI3K inhibition. Furthermore, we found that the combination of GDC-0941 and OSI-906 is synergistic in 8 lines from a panel of 18 TNBC cell lines. In these cell lines, inhibition of IGF1R further decreases the activity of downstream PI3K pathway components when PI3K is inhibited. Expression analysis of the panel of TNBC cell lines indicates that the expression levels of IGF2BP3 can be used as a potential predictor for sensitivity to the PI3K/IGF1R inhibitor combination. Our data show that combination therapy consisting of PI3K and IGF1R inhibitors could be beneficial in a subset of TNBCs. (C) 2016 AACR.