Department of Molecular and Translational Medicine, University of Brescia, Brescia 25123, Italy.
Department of Molecular and Translational Medicine, University of Brescia, Brescia 25123, Italy; Highly Specialized Laboratory, Diagnostic Department, ASST Spedali Civili of Brescia, Brescia, Italy.
Biochim Biophys Acta Gen Subj. 2023 Dec;1867(12):130470. doi: 10.1016/j.bbagen.2023.130470. Epub 2023 Sep 29.
The activation loop (A-loop) of kinases, a key regulatory region, is recurrently mutated in several kinase proteins in cancer resulting in dysregulated kinase activity and response to kinase inhibitors. FGFR1 receptor tyrosine kinase represents an important oncogene and therapeutic target for solid and hematological tumors. Here we investigate the biochemical and molecular effects of D647N mutation lying in the A-loop of FGFR1. When expressed in normal and tumoral in vitro cell models, FGFR1 is phosphorylated also in the absence of ligands, and this is accompanied by the activation of intracellular signaling. The expression of FGFR1 significantly increases single and collective migration of cancer cells in vitro and in vivo, when compared to FGFR1. FGFR1 expression exacerbates the aggressiveness of cancer cells, increasing their invasiveness in vitro and augmenting their pro-angiogenic capacity in vivo. Remarkably, the D647N mutation significantly increases the sensitivity of FGFR1 to the ATP-competitive inhibitor Erdafitinib suggesting the possibility that this mutation could become a specific target for the development of new inhibitors. Although further efforts are warranted for an exhaustive description of the activation mechanisms, for the identification of more specific inhibitors and for confirming the clinical significance of mutated FGFR1, overall our data demonstrate that the D647N substitution of FGFR1 is a novel pro-oncogenic activating mutation of the receptor that, when found in cancer patients, may anticipate good response to erdafitinib treatment.
激酶的激活环（A 环）是一个关键的调节区域，在癌症中的几种激酶蛋白中经常发生突变，导致激酶活性失调和对激酶抑制剂的反应。FGFR1 受体酪氨酸激酶是实体瘤和血液系统肿瘤的重要癌基因和治疗靶点。在这里，我们研究了 FGFR1 中的 A 环中 D647N 突变的生化和分子效应。当在正常和肿瘤体外细胞模型中表达时，FGFR1 在没有配体的情况下也被磷酸化，这伴随着细胞内信号的激活。与 FGFR1 相比，FGFR1 的表达显著增加了体外和体内癌细胞的单个和集体迁移。FGFR1 的表达加剧了癌细胞的侵袭性，增加了它们在体外的侵袭能力，并增强了它们在体内的促血管生成能力。值得注意的是，D647N 突变显著增加了 FGFR1 对 ATP 竞争性抑制剂 Erdafitinib 的敏感性，这表明这种突变可能成为开发新抑制剂的特定目标。尽管还需要进一步努力来详细描述激活机制、鉴定更特异性的抑制剂并确认突变 FGFR1 的临床意义，但总体而言，我们的数据表明，FGFR1 的 D647N 取代是受体的一种新的致癌激活突变，当在癌症患者中发现时，可能预示着对 Erdafitinib 治疗的良好反应。
