Ibrahim Milad, Illa-Bochaca Irineu, Fa'ak Faisal, Monson Kelsey R, Ferguson Robert, Lyu Chen, Vega-Saenz de Miera Eleazar, Johannet Paul, Chou Margaret, Mastroianni Justin, Darvishian Farbod, Kirchhoff Tomas, Zhong Judy, Krogsgaard Michelle, Osman Iman
Ronald O Perelman Department of Dermatology, NYU Grossman School of Medicine, New York, NY 10016, USA.
Department of Population Health, NYU Grossman School of Medicine, New York, NY 10016, USA.
Cancers (Basel). 2023 Dec 19;16(1):18. doi: 10.3390/cancers16010018.
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.
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.
We identified the KDR-Var genotype in 81/489 (37%) patients, and it was associated with a more angiogenic ( = 0.003) and immune-suppressive tumor phenotype. KDR-Var was also associated with decreased PFS to MAPKi ( = 0.022) and a trend with worse PFS to anti-PD1 therapy ( = 0.06). KDR-Var B16 murine models had increased average tumor volume ( = 0.0027) and decreased CD45 tumor-infiltrating lymphocytes ( = 0.0282). The anti-VEGFR treatment Lenvatinib reduced the tumor size of KDR-Var murine tumors ( = 0.0159), and KDR-Var cells showed synergistic cytotoxicity to the combination of dabrafenib and lenvatinib.
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.
我们之前报道，与普通人群相比，黑色素瘤患者激酶插入结构域受体（KDR）的致病种系变异发生率更高。在此，我们剖析这种基因型对黑色素瘤肿瘤生长动力学、肿瘤表型以及免疫检查点抑制剂（ICI）或靶向治疗反应的影响。
确定KDR基因型，并研究KDR Q472H变异（KDR-Var）、血管生成、肿瘤免疫表型以及对MAPK抑制或ICI治疗反应之间的关联。用KDR-Var或KDR野生型（KDR-WT）转染黑色素瘤B16细胞系，评估肿瘤动力学差异。我们还研究了KDR-Var对黑色素瘤细胞对VEGFR抑制与MAPKi联合治疗反应的影响。
我们在81/489（16.6%）例患者中鉴定出KDR-Var基因型，它与血管生成更多（P = 0.003）和免疫抑制性肿瘤表型相关。KDR-Var还与MAPKi的无进展生存期降低（P = 0.022）以及抗PD1治疗的无进展生存期更差的趋势相关（P = 0.06）。KDR-Var B16小鼠模型的平均肿瘤体积增加（P = 0.0027），肿瘤浸润淋巴细胞CD45减少（P = 0.0282）。抗VEGFR治疗乐伐替尼可减小KDR-Var小鼠肿瘤的大小（P = 0.0159），并且KDR-Var细胞对达拉非尼和乐伐替尼的联合显示出协同细胞毒性。
我们的数据证明种系KDR-Var在调节黑色素瘤行为（包括对治疗的反应）中起作用。我们的数据还表明抗血管生成治疗可能对携带这种基因型的患者有益，这需要在临床试验中进行测试。
