Department of Pharmacology, Gurgaon, Haryana, India.
Eur J Pharmacol. 2013 Jul 5;711(1-3):19-26. doi: 10.1016/j.ejphar.2013.04.016. Epub 2013 Apr 29.
Pharmacological intervention of epidermal growth factor receptor (EGFR) family members by antibodies or small molecule inhibitors has been one of the most successful approaches for anticancer therapy. However this therapy has its own limitations due to the development of resistance, over a period of time. One of the possible causes of the development of resistance to the therapy with EGFR inhibitors could be the simultaneous activation of parallel pathways. Both EGFR and insulin like growth factor-1 receptor (IGF-1R) pathways are reported to act reciprocal to each other and converge into the mitogen activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) pathways. Inhibiting one pathway alone may therefore not be sufficient and could be a cause of development of resistance. The other cause could be mutations of EGFR which would be less sensitive to the inhibitors. We, therefore, suggest that co-targeting IGF-1R and EGFR kinases by dual inhibitors can lead to improved efficacy and address the problems of resistance. In the present manuscript, we report the identification of a novel, small molecule dual EGFR/IGF-1R inhibitor, RBx10080307 which displayed in vitro activity at the molecular level and oral efficacy in mouse xenograft model. The compound also showed in vitro activity in an EGFR mutant cell line and may thus have the potential to show activity in resistant conditions. Additional efficacy studies are needed in EGFR resistant mouse cancer model and if found efficacious, this can be a major advantage over standalone erlotinib and other existing therapies.
表皮生长因子受体 (EGFR) 家族成员的药理学干预，无论是通过抗体还是小分子抑制剂，一直是癌症治疗中最成功的方法之一。然而，由于耐药性的发展，这种治疗方法存在自身的局限性。导致对 EGFR 抑制剂治疗产生耐药性的一个可能原因是平行途径的同时激活。据报道，EGFR 和胰岛素样生长因子-1 受体 (IGF-1R) 途径相互作用，并汇聚到丝裂原活化蛋白激酶 (MAPK) 和磷脂酰肌醇 3-激酶 (PI3K) 途径。因此，单独抑制一种途径可能是不够的，可能是耐药性发展的原因之一。另一个原因可能是 EGFR 的突变，使其对抑制剂的敏感性降低。因此，我们建议通过双重抑制剂共同靶向 IGF-1R 和 EGFR 激酶，可以提高疗效并解决耐药性问题。在本手稿中，我们报告了一种新型小分子双重 EGFR/IGF-1R 抑制剂 RBx10080307 的鉴定，该抑制剂在分子水平上表现出体外活性，并在小鼠异种移植模型中具有口服疗效。该化合物在 EGFR 突变细胞系中也表现出体外活性，因此可能具有在耐药条件下显示活性的潜力。在 EGFR 耐药性小鼠癌症模型中需要进行更多的疗效研究，如果发现有效，这将是优于厄洛替尼单药治疗和其他现有治疗方法的主要优势。
