Purpose: FGFR2 and FGFR3 show oncogenic activation in many cancer types, often through chromosomal fusion or extracellular domain mutation. FGFR2 and FGFR3 alterations are most prevalent in intrahepatic cholangiocarcinoma (ICC) and bladder cancers, respectively, and multiple selective reversible and covalent pan-FGFR tyrosine kinase inhibitors (TKIs) have been approved in these contexts. However, resistance, often due to acquired secondary mutations in the FGFR2/3 kinase domain, limits efficacy. Resistance is typically polyclonal, involving a spectrum of different mutations that most frequently affect the molecular brake and gatekeeper residues (N550 and V565 in FGFR2). Experimental design: Here we characterize the activity of the next-generation covalent FGFR inhibitor, KIN-3248, in preclinical models of FGFR2 fusion+ ICC harboring a series of secondary kinase domain mutations, in vitro and in vivo. We also test select FGFR3 alleles in bladder cancer models. Results: KIN-3248 exhibits potent selectivity for FGFR1-3 and retains activity against various FGFR2 kinase domain mutations, in addition to being effective against FGFR3 V555M and N540K mutations. Notably, KIN-3248 activity extends to the FGFR2 V565F gatekeeper mutation, which causes profound resistance to currently approved FGFR inhibitors. Combination treatment with EGFR or MEK inhibitors potentiates KIN-3248 efficacy in vivo, including in models harboring FGFR2 kinase domain mutations. Conclusions: Thus, KIN-3248 is a novel FGFR1-4 inhibitor whose distinct activity profile against FGFR kinase domain mutations highlights its potential for the treatment of ICC and other FGFR-driven cancers.

中文翻译：

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不可逆 FGFR 抑制剂 KIN-3248 克服了 FGFR2 激酶结构域突变。

目的：FGFR2 和 FGFR3 在许多癌症类型中显示出致癌激活作用，通常通过染色体融合或细胞外结构域突变实现。FGFR2 和 FGFR3 改变分别在肝内胆管癌 (ICC) 和膀胱癌中最为常见，多种选择性可逆共价泛 FGFR 酪氨酸激酶抑制剂 (TKI) 已在这些情况下获得批准。然而，通常由于 FGFR2/3 激酶结构域的获得性二次突变而产生的耐药性限制了疗效。耐药性通常是多克隆的，涉及一系列最常影响分子制动器和看门人残基（FGFR2 中的 N550 和 V565）的不同突变。实验设计：在这里，我们在体外和体内表征了下一代共价 FGFR 抑制剂 KIN-3248 在具有一系列二级激酶结构域突变的 FGFR2 融合+ ICC 临床前模型中的活性。我们还在膀胱癌模型中测试了选定的 FGFR3 等位基因。结果：KIN-3248 除了有效对抗 FGFR3 V555M 和 N540K 突变外，还对 FGFR1-3 表现出强大的选择性，并保留针对各种 FGFR2 激酶结构域突变的活性。值得注意的是，KIN-3248 的活性延伸至 FGFR2 V565F 看门人突变，该突变导致对目前批准的 FGFR 抑制剂产生严重耐药性。与 EGFR 或 MEK 抑制剂联合治疗可增强 KIN-3248 的体内疗效，包括在含有 FGFR2 激酶结构域突变的模型中。结论：因此，KIN-3248 是一种新型 FGFR1-4 抑制剂，其针对 FGFR 激酶结构域突变的独特活性特征凸显了其治疗 ICC 和其他 FGFR 驱动的癌症的潜力。