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

• Published in: Cancers Vol. 16; no. 1; p. 18
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 19-12-2023; MDPI
• Subjects: Angiogenesis; Animal models; Antimitotic agents; Antineoplastic agents; Cancer; Cancer therapies; Care and treatment; CD45 antigen; Cell growth; Clinical outcomes; Clinical trials; Cytotoxicity; Development and progression; Drug therapy; Gene expression; Genotypes; Growth; Immune checkpoint inhibitors; Kinases; Lymphocytes; MAP kinase; Medical prognosis; Melanoma; Microenvironments; Patient outcomes; Patients; PD-1 protein; Phenotypes; Remission; Tumor-infiltrating lymphocytes; Tumors; Vascular endothelial growth factor; Vascular endothelial growth factor receptors; New York; United States > US; KDR; targeted therapy; melanoma; germline; immune response
• ISSN: 2072-6694; 2072-6694
• 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.