Modulation of ErbB2 Blockade in ErbB2-Positive Cancers: The Role of ErbB2 Mutations and PHLDA1
Modulation of ErbB2 Blockade in ErbB2-Positive Cancers: The Role of ErbB2 Mutations and PHLDA1
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DOI：
10.1371/journal.pone.0106349
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发表时间：
2014-09-19
期刊：
影响因子：
3.7
通讯作者：
Halmos, Balazs
中科院分区：
文献类型：
--
作者：
Li, Guangyuan;Wang, Xiaoqi;Halmos, Balazs
我们着手研究ErbB 2酪氨酸激酶抑制剂（如拉帕替尼）在ErbB 2阳性乳腺癌和肺癌中的耐药性和敏感性的关键效应子。基于细胞的体外定点诱变拉帕替尼耐药模型鉴定了几种突变，包括看门人ErbB 2突变ErbB 2-T798 I，作为介导耐药。ErbB 2-T798 I工程化细胞模型确实显示出对拉帕替尼的耐药性，但对不可逆的EGFR/ErbB 2抑制剂PD 168393仍然敏感，这提示了克服耐药性的潜在替代治疗策略。基因表达谱研究确定了ErbB 2信号调节的一组选定的下游靶点，并将PHLDA 1定义为致癌ErbB 2信号抑制后立即下调的基因。我们发现PHLDA 1在原发性乳腺癌中显著下调，并且与ErbB 2阳性肿瘤相比，PHLDA 1在ErbB 2阴性肿瘤中的表达在统计学上显著降低，这与ErbB 2对其的调节一致。最后，PHLDA 1过表达阻断AKT信号传导，抑制细胞生长并增强拉帕替尼敏感性，进一步支持重要的负生长调节剂功能。我们的研究结果表明，PHLDA 1可能在ErbB 2驱动的肺癌和乳腺癌细胞中具有关键的抑制功能，更好地了解其功能可能指向新的治疗选择。总之，我们的研究定义了调节ErbB 2依赖性癌症对ErbB 2抑制的敏感性和耐药性的新方法。
We set out to study the key effectors of resistance and sensitivity to ErbB2 tyrosine kinase inhibitors, such as lapatinib in ErbB2-positive breast and lung cancers. A cell-based in vitro site-directed mutagenesis lapatinib resistance model identified several mutations, including the gatekeeper ErbB2 mutation ErbB2-T798I, as mediating resistance. ErbB2-T798I engineered cell models indeed show resistance to lapatinib but remain sensitive to the irreversible EGFR/ErbB2 inhibitor, PD168393, suggestive of potential alternative treatment strategies to overcome resistance. Gene expression profiling studies identified a select group of downstream targets regulated by ErbB2 signaling and define PHLDA1 as an immediately downregulated gene upon oncogenic ErbB2 signaling inhibition. We find significant down-regulation of PHLDA1 in primary breast cancer and PHLDA1 is statistically significantly less expressed in ErbB2 negative compared with ErbB2 positive tumors consistent with its regulation by ErbB2. Lastly, PHLDA1 overexpression blocks AKT signaling, inhibits cell growth and enhances lapatinib sensitivity further supporting an important negative growth regulator function. Our findings suggest that PHLDA1 might have key inhibitory functions in ErbB2 driven lung and breast cancer cells and a better understanding of its functions might point at novel therapeutic options. In summary, our studies define novel ways of modulating sensitivity and resistance to ErbB2 inhibition in ErbB2-dependent cancers.