Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts.
The Cancer Program, Broad Institute, Cambridge, Massachusetts.
Clin Cancer Res. 2024 May 15;30(10):2181-2192. doi: 10.1158/1078-0432.CCR-23-3588.
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 (TKI) 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).
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.
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.
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.
FGFR2 和 FGFR3 在许多癌症类型中表现出致癌激活，通常通过染色体融合或细胞外结构域突变。FGFR2 和 FGFR3 的改变分别在肝内胆管癌（ICC）和膀胱癌中最为常见，并且在这些情况下已经批准了多种选择性可逆和共价泛 FGFR 酪氨酸激酶抑制剂（TKI）。然而，耐药性通常由于 FGFR2/3 激酶结构域获得性继发性突变而受到限制。耐药性通常是多克隆的，涉及一系列不同的突变，这些突变最常影响分子刹车和门控残基（FGFR2 中的 N550 和 V565）。
在这里，我们在体外和体内研究了一系列继发性激酶结构域突变的 FGFR2 融合+ICC 的临床前模型中，鉴定了下一代共价 FGFR 抑制剂 KIN-3248 的活性。我们还在膀胱癌模型中测试了几种 FGFR3 等位基因。
KIN-3248 对 FGFR1-3 具有强大的选择性，保留了对各种 FGFR2 激酶结构域突变的活性，此外对 FGFR3 V555M 和 N540K 突变也有效。值得注意的是，KIN-3248 的活性延伸到 FGFR2 V565F 门控突变，这导致对目前批准的 FGFR 抑制剂产生深刻的耐药性。与 EGFR 或 MEK 抑制剂联合治疗可增强 KIN-3248 在体内的疗效，包括在携带 FGFR2 激酶结构域突变的模型中。
因此，KIN-3248 是一种新型的 FGFR1-4 抑制剂，其对 FGFR 激酶结构域突变的独特活性谱突出了其在治疗 ICC 和其他 FGFR 驱动的癌症方面的潜力。
