Schöffski Patrick, Gebreyohannes Yemarshet, Van Looy Thomas, Manley Paul, Growney Joseph D, Squires Matthew, Wozniak Agnieszka
Department of General Medical Oncology, University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium.
Research Unit Laboratory of Experimental Oncology, Department of Oncology, KU Leuven, Herestraat 49, 3000 Leuven, Belgium.
Biomedicines. 2022 May 13;10(5):1135. doi: 10.3390/biomedicines10051135.
Advanced gastrointestinal stromal tumors (GIST) are typically treated with tyrosine kinase inhibitors, and imatinib is the most commonly used standard of care in first line treatments. The use of this and other tyrosine kinase inhibitors is associated with objective tumor responses and prolongation of progression-free and overall survival, but the treatment of metastatic disease is non-curative due to the selection or acquisition of secondary mutations and the activation of alternative kinase signaling pathways, leading to resistance and disease progression after an initial response. The present preclinical study evaluated the potential use of the fibroblast growth factor receptor inhibitors infigratinib and dovitinib alone or in combination with the mitogen-activated protein kinase inhibitor binimetinib in mouse models of GIST with different sensitivity or resistance to imatinib. Patient- and cell-line-derived GIST xenografts were established by bilateral, subcutaneous transplantation of human GIST tissue in female adult NMRI mice. The mice were treated with dovitinib, infigratinib, or binimetinib, either alone or in combination with imatinib. The safety of treated animals was assessed by well-being inspection and body weight measurement. Antitumor effects were assessed by caliper-based tumor measurement. H&E staining and immunohistochemistry were used for assessing anti-mitotic and pro-apoptotic activity of the experimental treatments. Western blotting was used for assessing effects of the agents on kinase signaling pathways. Anti-angiogenic activity was assessed by measuring tumor vessel density. Dovitinib was found to have antitumor efficacy in GIST xenografts characterized by different imatinib resistance patterns. Dovitinib had better efficacy than imatinib (both at standard and increased dose) and was found to be well tolerated. Dovitinib had better efficacy in a exon 9 mutant model, highlighting a role of patient selection in clinical GIST trials with the agent. In a model with exon 11 and 17 mutations, dovitinib induced tumor necrosis, most likely due to anti-angiogenic effects. Additive effects combining dovitinib with binimetinib were limited.
晚期胃肠道间质瘤（GIST）通常采用酪氨酸激酶抑制剂进行治疗，伊马替尼是一线治疗中最常用的标准治疗药物。使用这种及其他酪氨酸激酶抑制剂可带来客观的肿瘤反应，并延长无进展生存期和总生存期，但转移性疾病的治疗无法治愈，因为会出现继发性突变的选择或获得以及替代激酶信号通路的激活，导致在初始反应后产生耐药性和疾病进展。本临床前研究评估了成纤维细胞生长因子受体抑制剂英菲格拉替尼和多韦替尼单独或与丝裂原活化蛋白激酶抑制剂比美替尼联合在对伊马替尼具有不同敏感性或耐药性的GIST小鼠模型中的潜在用途。通过将人GIST组织双侧皮下移植到成年雌性NMRI小鼠中，建立患者和细胞系来源的GIST异种移植模型。小鼠分别接受多韦替尼、英菲格拉替尼或比美替尼单独治疗，或与伊马替尼联合治疗。通过健康检查和体重测量评估治疗动物的安全性。通过卡尺测量肿瘤大小评估抗肿瘤效果。苏木精-伊红（H&E）染色和免疫组织化学用于评估实验治疗的抗有丝分裂和促凋亡活性。蛋白质免疫印迹法用于评估药物对激酶信号通路的影响。通过测量肿瘤血管密度评估抗血管生成活性。发现多韦替尼在具有不同伊马替尼耐药模式的GIST异种移植模型中具有抗肿瘤疗效。多韦替尼的疗效优于伊马替尼（标准剂量和增加剂量时均如此），且耐受性良好。多韦替尼在9号外显子突变模型中疗效更佳，突出了在该药物的临床GIST试验中患者选择的作用。在一个具有11号和17号外显子突变的模型中，多韦替尼诱导肿瘤坏死，最可能是由于抗血管生成作用。多韦替尼与比美替尼联合的相加作用有限。
