Despite recent advances in treatment of non-small cell lung cancer (NSCLC), prognosis still remains poor and new therapeutic approaches are needed. Studies demonstrate the importance of the EGFR/HER-receptor family in NSCLC growth, as well as that of other tumors. Recently, HER3 is receiving increased attention because of its role in drug resistance and aggressive growth. Activation of overexpressed G-protein-coupled receptors (GPCR) can also initiate growth by transactivating EGFR/HER-family members. GPCR transactivation of EGFR has been extensively studied, but little is known of its ability to transactivate other EGFR/HER-members, especially HER3. To address this, we studied the ability of bombesin receptor (BnR) activation to transactivate all EGFR/HER-family members and their principal downstream signaling cascades, the PI3K/Akt- and MAPK/ERK-pathways, in human NSCLC cell-lines. In all three cell-lines studied, which possessed EGFR, HER2 and HER3, Bn rapidly transactivated EGFR, HER2 and HER3, as well as Akt and ERK. Immunoprecipitation studies revealed Bn-induced formation of both HER3/EGFR- and HER3/HER2-heterodimers. Specific EGFR/HER3 antibodies or siRNA-knockdown of EGFR and HER3, demonstrated Bn-stimulated activation of EGFR/HER members is initially through HER3, not EGFR. In addition, specific inhibition of HER3, HER2 or MAPK, abolished Bn-stimulated cell-growth, while neither EGFR nor Akt inhibition had an effect. These results show HER3 transactivation mediates all growth effects of BnR activation through MAPK. These results raise the possibility that targeting HER3 alone or with GPCR activation and its signal cascades, may be a novel therapeutic approach in NSCLC. This is especially relevant with the recent development of HER3-blocking antibodies.

中文翻译：

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神经肽蛙皮素受体激活通过具有MAPK依赖性机制的HER3刺激肺癌细胞的生长。

尽管最近在非小细胞肺癌（NSCLC）的治疗方面取得了进展，但预后仍然很差，需要新的治疗方法。研究表明，EGFR / HER受体家族在NSCLC以及其他肿瘤中的重要性。最近，由于HER3在耐药性和侵袭性生长中的作用，因此受到越来越多的关注。过表达的G蛋白偶联受体（GPCR）的激活也可以通过反式激活EGFR / HER家族成员来启动生长。EGFR的GPCR反式激活已被广泛研究，但对其反式激活其他EGFR / HER成员（尤其是HER3）的能力知之甚少。为了解决这个问题，我们研究了铃蟾毒素受体（BnR）激活能够激活所有EGFR / HER家族成员及其主要下游信号传导级联的能力，人NSCLC细胞系中的PI3K / Akt和MAPK / ERK途径。在所有三个具有EGFR，HER2和HER3的细胞系中，Bn快速激活了EGFR，HER2和HER3以及Akt和ERK。免疫沉淀研究表明，Bn诱导了HER3 / EGFR-和HER3 / HER2-异二聚体的形成。特定的EGFR / HER3抗体或EGFR和HER3的siRNA敲低，证明Bn刺激的EGFR / HER成员的激活最初是通过HER3，而不是EGFR。此外，对HER3，HER2或MAPK的特异性抑制作用消除了Bn刺激的细胞生长，而EGFR和Akt抑制作用均无效。这些结果表明，HER3反式激活通过MAPK介导了BnR激活的所有生长作用。这些结果增加了将HER3单独靶向或通过GPCR激活及其信号级联的可能性，在非小细胞肺癌中可能是一种新颖的治疗方法。这与HER3阻断抗体的最新发展特别相关。