Trastuzumab-resistant cells rely on a HER2-PI3K-FoxO-survivin axis and are sensitive to PI3K inhibitors.
Trastuzumab-resistant cells rely on a HER2-PI3K-FoxO-survivin axis and are sensitive to PI3K inhibitors.
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DOI：
10.1158/0008-5472.can-12-2440
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发表时间：
2013-02-01
期刊：
影响因子：
11.2
通讯作者：
Arteaga CL
中科院分区：
文献类型：
--
作者：
Chakrabarty A;Bhola NE;Sutton C;Ghosh R;Kuba MG;Dave B;Chang JC;Arteaga CL
曲妥珠单抗抗体获批用于治疗HER 2（ERBB 2）过表达乳腺癌患者。这些肿瘤中的很大一部分是固有耐药或获得性耐药，使药物无效。耐药性的发生归因于抗体未能抑制由HER 2网络激活的磷脂酰肌醇-3激酶（PI 3 K）。在此，我们研究了PI 3 K阻断在曲妥珠单抗耐药乳腺癌细胞系中的作用。用pan-PI 3 K抑制剂XL 147和曲妥珠单抗治疗降低了增殖和pAKT水平，触发曲妥珠单抗耐药细胞的凋亡。与XL 147单药相比，联合用药对曲妥珠单抗耐药肿瘤异种移植物显示出上级抗肿瘤作用。此外，XL 147和曲妥珠单抗治疗降低了体外和体内曲妥珠单抗耐药细胞中的癌症干细胞（CSC）分数。这些作用与FoxO介导的抗凋亡基因生存素（BIRC 5）和CSC相关细胞因子IL-8的转录抑制有关。RNAi介导的或药物抑制生存素恢复敏感性曲妥珠单抗耐药细胞。在一组接受曲妥珠单抗治疗的HER 2过表达乳腺癌患者中，治疗前较高的生存素RNA肿瘤水平与治疗反应不良相关。总之，我们的研究结果表明，生存素阻断是曲妥珠单抗治疗反应所必需的，并且通过曲妥珠单抗和PI 3 K抑制剂的组合，可以减少HER 2+肿瘤中的CSC，从而潜在地预防对抗HER 2治疗的获得性耐药性。
The antibody trastuzumab is approved for treatment of patients with HER2 (ERBB2)-overexpressing breast cancer. A significant fraction of these tumors are either intrinsically resistant or acquire resistance rendering the drug ineffective. The development of resistance has been attributed to failure of the antibody to inhibit phosphatidylinositol-3 kinase (PI3K), which is activated by the HER2 network. Herein, we examined the effects of PI3K blockade in trastuzumab-resistant breast cancer cell lines. Treatment with the pan-PI3K inhibitor XL147 and trastuzumab reduced proliferation and pAKT levels, triggering apoptosis of trastuzumab-resistant cells. Compared to XL147 alone, the combination exhibited a superior antitumor effect against trastuzumab-resistant tumor xenografts. Further, treatment with XL147 and trastuzumab reduced the cancer stem cell (CSC) fraction within trastuzumab-resistant cells both in vitro and in vivo. These effects were associated with FoxO-mediated inhibition of transcription of the anti-apoptosis gene survivin (BIRC5) and the CSC-associated cytokine IL-8. RNAi-mediated or pharmacological inhibition of survivin restored sensitivity to trastuzumab in resistant cells. In a cohort of patients with HER2-overexpressing breast cancer treated with trastuzumab, higher pre-treatment tumor levels of survivin RNA correlated with poor response to therapy. Together, our results suggest that survivin blockade is required for therapeutic responses to trastuzumab and that by combining trastuzumab and PI3K inhibitors CSCs can be reduced within HER2+ tumors, potentially preventing acquired resistance to anti-HER2 therapy.