文章：

激酶插入域受体Q472H致病性种系变异对黑色素瘤肿瘤生长及患者治疗结局的影响

Kinase Insert Domain Receptor Q472H Pathogenic Germline Variant Impacts Melanoma Tumor Growth and Patient Treatment Outcomes

原文发布日期：19 December 2023

DOI: 10.3390/cancers16010018

类型: Article

开放获取: 是

英文摘要：

Background: We previously reported a higher incidence of a pathogenic germline variant in the kinase insert domain receptor (KDR) in melanoma patients compared to the general population. Here, we dissect the impact of this genotype on melanoma tumor growth kinetics, tumor phenotype, and response to treatment with immune checkpoint inhibitors (ICIs) or targeted therapy. Methods: The KDR genotype was determined and the associations between the KDR Q472H variant (KDR-Var), angiogenesis, tumor immunophenotype, and response to MAPK inhibition or ICI treatment were examined. Melanoma B16 cell lines were transfected with KDR-Var or KDR wild type (KDR-WT), and the differences in tumor kinetics were evaluated. We also examined the impact of KDR-Var on the response of melanoma cells to a combination of VEGFR inhibition with MAPKi. Results: We identified the KDR-Var genotype in 81/489 (37%) patients, and it was associated with a more angiogenic (p= 0.003) and immune-suppressive tumor phenotype. KDR-Var was also associated with decreased PFS to MAPKi (p= 0.022) and a trend with worse PFS to anti-PD1 therapy (p= 0.06). KDR-Var B16 murine models had increased average tumor volume (p= 0.0027) and decreased CD45 tumor-infiltrating lymphocytes (p= 0.0282). The anti-VEGFR treatment Lenvatinib reduced the tumor size of KDR-Var murine tumors (p= 0.0159), and KDR-Var cells showed synergistic cytotoxicity to the combination of dabrafenib and lenvatinib. Conclusions: Our data demonstrate a role of germline KDR-Var in modulating melanoma behavior, including response to treatment. Our data also suggest that anti-angiogenic therapy might be beneficial in patients harboring this genotype, which needs to be tested in clinical trials.

摘要翻译： 

背景：我们先前报道过，与普通人群相比，黑色素瘤患者中激酶插入结构域受体（KDR）致病性胚系变异的发生率更高。本研究旨在剖析该基因型对黑色素瘤肿瘤生长动力学、肿瘤表型以及对免疫检查点抑制剂（ICIs）或靶向治疗反应的影响。 方法：测定KDR基因型，并分析KDR Q472H变异体（KDR-Var）与血管生成、肿瘤免疫表型以及对MAPK抑制剂或ICI治疗反应之间的关联。将KDR-Var或KDR野生型（KDR-WT）转染至黑色素瘤B16细胞系，评估肿瘤生长动力学的差异。同时，我们还研究了KDR-Var对黑色素瘤细胞响应VEGFR抑制剂联合MAPKi治疗的影响。 结果：在489例患者中，81例（37%）检测到KDR-Var基因型，该基因型与更强的血管生成（p=0.003）和免疫抑制性肿瘤表型相关。KDR-Var还与MAPKi治疗的无进展生存期（PFS）缩短相关（p=0.022），并且在抗PD1治疗中显示出PFS更差的趋势（p=0.06）。KDR-Var B16小鼠模型的平均肿瘤体积增大（p=0.0027），肿瘤浸润CD45淋巴细胞减少（p=0.0282）。抗VEGFR治疗药物乐伐替尼能减小KDR-Var小鼠肿瘤的体积（p=0.0159），且KDR-Var细胞对达拉非尼联合乐伐替尼表现出协同细胞毒性。 结论：我们的数据证明了胚系KDR-Var在调控黑色素瘤行为（包括对治疗的反应）中的作用。数据还提示，抗血管生成治疗可能对携带此基因型的患者有益，这有待临床试验进一步验证。

原文链接：

Kinase Insert Domain Receptor Q472H Pathogenic Germline Variant Impacts Melanoma Tumor Growth and Patient Treatment Outcomes