Targeting both Notch and ErbB-2 signalling pathways is required for prevention of ErbB-2-positive breast tumour recurrence.
Targeting both Notch and ErbB-2 signalling pathways is required for prevention of ErbB-2-positive breast tumour recurrence.
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DOI：
10.1038/bjc.2011.321
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发表时间：
2011-09-06
影响因子：
8.8
通讯作者：
Osipo, C.
中科院分区：
文献类型：
--
作者：
Pandya, K.;Meeke, K.;Clementz, A. G.;Rogowski, A.;Roberts, J.;Miele, L.;Albain, K. S.;Osipo, C.
我们报道了Notch-1，一个有效的乳腺癌癌基因，在曲妥珠单抗作用下被激活，并在体外参与曲妥珠单抗耐药。我们试图确定Notch抑制剂(γ分泌酶抑制剂)和曲妥珠单抗联合治疗体内曲妥珠单抗敏感和曲妥珠单抗耐药、ErbB-2阳性的BT474乳腺肿瘤的临床前益处。我们还研究了拉帕替尼联合GSI是否能诱导ErbB-2阳性乳腺癌的肿瘤消退。我们从曲妥珠单抗或拉帕替尼敏感和曲妥珠单抗耐药的BT474细胞中产生了原位乳腺肿瘤异种移植瘤。我们研究了两种不同的GSI，LY411MRK575和 -003的体内抗肿瘤活性。我们的研究结果显示，在敏感肿瘤中，曲妥珠单抗联合GSI可完全预防(MRK-003GSI)或显著减少(LY 411 575GSI)乳腺癌复发。此外，联合应用拉帕替尼和MRK-003GSI可显著减少肿瘤生长。此外，GSI部分逆转了耐药肿瘤中的曲妥珠单抗耐药性。我们的数据表明，联合抑制Notch和ErbB-2信号通路可以降低ErbB-2阳性乳腺肿瘤的复发率，并可能对复发的曲妥珠单抗耐药疾病的治疗有利。
We reported that Notch-1, a potent breast oncogene, is activated in response to trastuzumab and contributes to trastuzumab resistance in vitro. We sought to determine the preclinical benefit of combining a Notch inhibitor (γ-secretase inhibitor (GSI)) and trastuzumab in both trastuzumab-sensitive and trastuzumab-resistant, ErbB-2-positive, BT474 breast tumours in vivo. We also studied if the combination therapy of lapatinib plus GSI can induce tumour regression of ErbB-2-positive breast cancer. We generated orthotopic breast tumour xenografts from trastuzumab- or lapatinib-sensitive and trastuzumab-resistant BT474 cells. We investigated the antitumour activities of two distinct GSIs, LY 411 575 and MRK-003, in vivo. Our findings showed that combining trastuzumab plus a GSI completely prevented (MRK-003 GSI) or significantly reduced (LY 411 575 GSI) breast tumour recurrence post-trastuzumab treatment in sensitive tumours. Moreover, combining lapatinib plus MRK-003 GSI showed significant reduction of tumour growth. Furthermore, a GSI partially reversed trastuzumab resistance in resistant tumours. Our data suggest that a combined inhibition of Notch and ErbB-2 signalling pathways could decrease recurrence rates for ErbB-2-positive breast tumours and may be beneficial in the treatment of recurrent trastuzumab-resistant disease.
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