Zhong-Shan-Men Inpatient Department; National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention and Therapy; Tianjin Medical University Cancer Institute and Hospital Tianjin, 300060, China.
Clinical Immunology and Rheumatology, Medicine Department of University of Alabama at Birmingham, Birmingham, Alabama, USA.
Sci Rep. 2016 Sep 9;6:32809. doi: 10.1038/srep32809.
Blockade of the epidermal growth factor receptor (EGFR) by EGFR tyrosine kinase inhibitors is insufficient for effective anti-tumor activity because the reactivation of the ErbB3 signaling pathway significantly contributes to activating the consequent phosphoinositide 3-kinase (PI3K)/Akt signaling pathway. Combinatorial therapies including ErbB3 targeting may ameliorate tumor responses to anti-EGFR therapies. In the present study, we found that in BxPC-3 and L3.6pl cells, which highly expressed the ErbB3 receptor, significant reduction in cell viability, induction of apoptosis were observed when treated with a combination of erlotinib and PF compared to either agent alone. Moreover, in ErbB3-expressing BxPC-3, L3.6pl and S2VP10 cell lines, the inhibition of ErbB3/PI3K/Akt phosphorylation were observed when treated with PF. Most strikingly, both EGFR/MAPK/Erk and ErbB3/PI3K/Akt activitions were substantially suppressed when treated with the combination of PF and erlotinib. However, in the ErbB3-deficient cell line MIAPaCa-2, no such effects were observed with similar treatments. Most importantly, these in vitro results were replicated in nude mouse transplanted tumor models. Taken together, our findings show that PF enhances the effect of erlotinib in ErbB3-expressing pancreatic cancer cells by directly suppressing ErbB3 activation, and PF in combination with erlotinib is much more effective as an antitumor agent compared with either agent alone.
表皮生长因子受体 (EGFR) 的酪氨酸激酶抑制剂阻断不足以实现有效的抗肿瘤活性，因为 ErbB3 信号通路的再激活显著有助于激活随后的磷酸肌醇 3-激酶 (PI3K)/Akt 信号通路。包括 ErbB3 靶向在内的联合疗法可能改善肿瘤对抗 EGFR 治疗的反应。在本研究中，我们发现，在高度表达 ErbB3 受体的 BxPC-3 和 L3.6pl 细胞中，与单独使用任一药物相比，用厄洛替尼和 PF 联合处理时，细胞活力显著降低，诱导细胞凋亡。此外，在表达 ErbB3 的 BxPC-3、L3.6pl 和 S2VP10 细胞系中，用 PF 处理时观察到 ErbB3/PI3K/Akt 磷酸化的抑制。最引人注目的是，用 PF 和厄洛替尼联合处理时，EGFR/MAPK/Erk 和 ErbB3/PI3K/Akt 的激活均受到显著抑制。然而，在 ErbB3 缺失细胞系 MIAPaCa-2 中，用类似处理则观察不到这种作用。最重要的是，这些体外结果在裸鼠移植瘤模型中得到了复制。总之，我们的研究结果表明，PF 通过直接抑制 ErbB3 激活增强了厄洛替尼在表达 ErbB3 的胰腺癌细胞中的作用，并且与单独使用任一药物相比，PF 联合厄洛替尼作为抗肿瘤药物更为有效。
