HER2YVMA drives rapid development of adenosquamous lung tumors in mice that are sensitive to BIBW2992 and rapamycin combination therapy
HER2YVMA drives rapid development of adenosquamous lung tumors in mice that are sensitive to BIBW2992 and rapamycin combination therapy
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DOI：
10.1073/pnas.0808930106
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发表时间：
2009-01-13
影响因子：
11.1
通讯作者：
Wong, Kwok-Kin
中科院分区：
文献类型：
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作者：
Perera, Samanthi A.;Li, Danan;Wong, Kwok-Kin
HER2激酶结构域的突变已经在人类临床肺癌标本中被发现。本研究表明，小鼠肺上皮中最常见的HER2突变体（HER2(YVMA)）的诱导表达可导致局限于近端和远端细支气管的侵袭性腺鳞癌。HER2YVMA的持续表达对肿瘤维持至关重要，这表明HER2在肺腺鳞癌发生中起关键作用。临床前研究评估了埃洛替尼、曲妥珠单抗、BIBW2992和/或雷帕霉素对HER2（YVMA）转基因小鼠或有肿瘤负担的H1781异种移植物的体内作用，结果显示，BIBW2992和雷帕霉素联合使用是最有效的治疗模式，可显著缩小肿瘤。免疫组织化学分析显示，BIBW2992和雷帕霉素联合治疗肺肿瘤后，MAPK和Akt/mTOR信号轴上下游臂的蛋白磷酸化水平均下降，表明这些途径受到抑制。基于这些发现，在肿瘤表达HER2突变的非小细胞肺癌患者中进行BIBW2992/雷帕霉素联合临床试验是有必要的。
Mutations in the HER2 kinase domain have been identified in human clinical lung cancer specimens. Here we demonstrate that inducible expression of the most common HER2 mutant (HER2(YVMA)) in mouse lung epithelium causes invasive adenosquamous carcinomas restricted to proximal and distal bronchioles. Continuous expression of HER2YVMA is essential for tumor maintenance, suggesting a key role for HER2 in lung adenosquamous tumorigenesis. Preclinical studies assessing the in vivo effect of erlotinib, trastuzumab, BIBW2992, and/or rapamycin on HER2(YVMA) transgenic mice or H1781 xenografts with documented tumor burden revealed that the combination of BIBW2992 and rapamycin is the most effective treatment paradigm causing significant tumor shrinkage. Immunohistochemical analysis of lung tumors treated with BIBW2992 and rapamycin combination revealed decreased phosphorylation levels for proteins in both upstream and downstream arms of MAPK and Akt/mTOR signaling axes, indicating inhibition of these pathways. Based on these findings, clinical testing of the BIBW2992/rapamycin combination in non-small cell lung cancer patients with tumors expressing HER2 mutations is warranted.