Division of Molecular Pathology, The Institute of Cancer Research, London SM2 5NG, UK.
Institute of Structural and Molecular Biology, Division of Biosciences, University College London, London WC1E 6BT, UK.
Int J Mol Sci. 2020 May 1;21(9):3214. doi: 10.3390/ijms21093214.
Selective FGFR inhibitors such as infigratinib (BGJ398) and erdafitinib (JNJ-42756493) have been evaluated in clinical trials for cancers with FGFR3 molecular alterations, particularly in urothelial carcinoma patients. However, a substantial proportion of these patients (up to 50%) display intrinsic resistance to these drugs and receive minimal clinical benefit. There is thus an unmet need for alternative therapeutic strategies to overcome primary resistance to selective FGFR inhibitors. In this study, we demonstrate that cells expressing cancer-associated activating FGFR3 mutants and the FGFR3-TACC3 fusion showed primary resistance to infigratinib in long-term colony formation assays in both NIH-3T3 and urothelial carcinoma models. We find that expression of these FGFR3 molecular alterations resulted in elevated constitutive Src activation compared to wildtype FGFR3 and that cells co-opted this pathway as a means to achieve intrinsic resistance to infigratinib. Targeting the Src pathway with low doses of the kinase inhibitor dasatinib synergistically sensitized multiple urothelial carcinoma lines harbouring endogenous FGFR3 alterations to infigratinib. Our data provide preclinical rationale that supports the use of dasatinib in combination with selective FGFR inhibitors as a means to overcome intrinsic drug resistance in the salvage therapy setting in urothelial cancer patients with FGFR3 molecular alterations.
选择性 FGFR 抑制剂，如英菲格拉替尼（BGJ398）和厄达替尼（JNJ-42756493），已在具有 FGFR3 分子改变的癌症的临床试验中进行了评估，特别是在膀胱癌患者中。然而，相当一部分患者（高达 50%）对这些药物存在内在耐药性，临床获益有限。因此，需要替代治疗策略来克服对选择性 FGFR 抑制剂的原发性耐药。在这项研究中，我们证明了表达癌相关激活 FGFR3 突变体和 FGFR3-TACC3 融合的细胞在 NIH-3T3 和膀胱癌模型中的长期集落形成试验中对英菲格拉替尼表现出原发性耐药。我们发现，与野生型 FGFR3 相比，这些 FGFR3 分子改变的表达导致了组成型Src 激活的升高，并且细胞将该途径作为实现对英菲格拉替尼内在耐药的手段。用低剂量激酶抑制剂达沙替尼靶向 Src 途径协同增敏多种携带内源性 FGFR3 改变的膀胱癌系对英菲格拉替尼的敏感性。我们的数据提供了临床前依据，支持在 FGFR3 分子改变的膀胱癌患者的挽救治疗中，将达沙替尼与选择性 FGFR 抑制剂联合使用，作为克服内在药物耐药性的一种手段。
