Rogaratinib: A potent and selective pan-FGFR inhibitor with broad antitumor activity in FGFR-overexpressing preclinical cancer models
Rogaratinib: A potent and selective pan-FGFR inhibitor with broad antitumor activity in FGFR-overexpressing preclinical cancer models
复制标题
DOI：
10.1002/ijc.32224
复制
发表时间：
2019-09-01
影响因子：
6.4
通讯作者：
Ziegelbauer, Karl
中科院分区：
文献类型：
--
作者：
Gruenewald, Sylvia;Politz, Oliver;Ziegelbauer, Karl
成纤维细胞生长因子信号传导的异常激活与多种癌症的发生有关，包括鳞状细胞肺癌、鳞状细胞头颈癌、结直肠癌和膀胱癌。因此，成纤维细胞生长因子受体（FGFR）为新型癌症治疗提供了有希望的靶标。在这里，我们在多种临床前癌症模型的生化、细胞和体内功效研究中评估了新型泛 FGFR 抑制剂罗加替尼的活性。体外激酶活性测定表明，罗加替尼有效且选择性地抑制 FGFR 1、2、3 和 4 的活性。与此相符，罗加替尼可减少各种癌症类型（包括肺癌、乳腺癌、结肠癌和膀胱癌）的 FGFR 成瘾癌细胞系的增殖。在几种 FGFR 扩增细胞系中，罗加替尼治疗可中断 FGFR 和 ERK 磷酸化，这表明抗增殖作用是由 FGFR/ERK 通路抑制介导的。此外，罗加替尼在多种以 FGFR 过表达为特征的细胞系和患者来源的异种移植模型中表现出强大的体内功效。观察到的罗加替尼疗效与 FGFR mRNA 表达水平密切相关。这些有希望的结果保证了罗加替尼的进一步开发，目前正在进行临床试验（标识符：NCT01976741、NCT03410693、NCT03473756）。
Aberrant activation in fibroblast growth factor signaling has been implicated in the development of various cancers, including squamous cell lung cancer, squamous cell head and neck carcinoma, colorectal and bladder cancer. Thus, fibroblast growth factor receptors (FGFRs) present promising targets for novel cancer therapeutics. Here, we evaluated the activity of a novel pan-FGFR inhibitor, rogaratinib, in biochemical, cellular and in vivo efficacy studies in a variety of preclinical cancer models. In vitro kinase activity assays demonstrate that rogaratinib potently and selectively inhibits the activity of FGFRs 1, 2, 3 and 4. In line with this, rogaratinib reduced proliferation in FGFR-addicted cancer cell lines of various cancer types including lung, breast, colon and bladder cancer. FGFR and ERK phosphorylation interruption by rogaratinib treatment in several FGFR-amplified cell lines suggests that the anti-proliferative effects are mediated by FGFR/ERK pathway inhibition. Furthermore, rogaratinib exhibited strong in vivo efficacy in several cell line- and patient-derived xenograft models characterized by FGFR overexpression. The observed efficacy of rogaratinib strongly correlated with FGFR mRNA expression levels. These promising results warrant further development of rogaratinib and clinical trials are currently ongoing ( Identifiers: NCT01976741, NCT03410693, NCT03473756).