Kinase Insert Domain Receptor Q472H Pathogenic Germline Variant Impacts Melanoma Tumor Growth and Patient Treatment Outcomes
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 wi...
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| Published in: | Cancers Vol. 16; no. 1; p. 18 |
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| Abstract | 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. |
|---|---|
| AbstractList | 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. Simple SummaryDespite the improvement in melanoma treatment over the last decade, there is still a need for developing new treatment strategies that can achieve complete and durable remission. Herein, we provide evidence that the kinase domain receptor (KDR) pathogenic germline variant Q472H confers more angiogenic and proliferative tumors, a more immune-suppressive microenvironment, and more resistance to therapy. Data suggest that anti-angiogenic therapy might be beneficial in patients harboring this genotype.AbstractBackground: 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. Despite the improvement in melanoma treatment over the last decade, there is still a need for developing new treatment strategies that can achieve complete and durable remission. Herein, we provide evidence that the kinase domain receptor (KDR) pathogenic germline variant Q472H confers more angiogenic and proliferative tumors, a more immune-suppressive microenvironment, and more resistance to therapy. Data suggest that anti-angiogenic therapy might be beneficial in patients harboring this genotype. 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. BACKGROUNDWe 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.METHODSThe 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.RESULTSWe 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.CONCLUSIONSOur 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. Despite the improvement in melanoma treatment over the last decade, there is still a need for developing new treatment strategies that can achieve complete and durable remission. Herein, we provide evidence that the kinase domain receptor (KDR) pathogenic germline variant Q472H confers more angiogenic and proliferative tumors, a more immune-suppressive microenvironment, and more resistance to therapy. Data suggest that anti-angiogenic therapy might be beneficial in patients harboring this genotype. 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. |
| Audience | Academic |
| Author | Monson, Kelsey R Kirchhoff, Tomas Mastroianni, Justin Fa'ak, Faisal Vega-Saenz de Miera, Eleazar Ferguson, Robert Zhong, Judy Illa-Bochaca, Irineu Chou, Margaret Johannet, Paul Osman, Iman Ibrahim, Milad Lyu, Chen Darvishian, Farbod Krogsgaard, Michelle |
| AuthorAffiliation | 2 Department of Population Health, NYU Grossman School of Medicine, New York, NY 10016, USA; kelsey.monson@nyulangone.org (K.R.M.); robert.ferguson@nyulangone.org (R.F.); chen.lyu@nyulangone.org (C.L.); tomas.kirchhoff@nyulangone.org (T.K.); judy.zhong@nyulangone.org (J.Z.) 4 Interdisciplinary Melanoma Cooperative Group, NYU Langone Health, 522 First Ave, New York, NY 10016, USA 1 Ronald O Perelman Department of Dermatology, NYU Grossman School of Medicine, New York, NY 10016, USA; miladadelmilad.ibrahim@nyulangone.org (M.I.); irineu.illabochaca@nyulangone.org (I.I.-B.); eleazar.vega-saenzdemiera@nyulangone.org (E.V.-S.d.M.) 3 Department of Pathology, NYU Grossman School of Medicine, New York, NY 10016, USA michelle.krogsgaard@nyulangone.org (M.K.) |
| AuthorAffiliation_xml | – name: 2 Department of Population Health, NYU Grossman School of Medicine, New York, NY 10016, USA; kelsey.monson@nyulangone.org (K.R.M.); robert.ferguson@nyulangone.org (R.F.); chen.lyu@nyulangone.org (C.L.); tomas.kirchhoff@nyulangone.org (T.K.); judy.zhong@nyulangone.org (J.Z.) – name: 4 Interdisciplinary Melanoma Cooperative Group, NYU Langone Health, 522 First Ave, New York, NY 10016, USA – name: 3 Department of Pathology, NYU Grossman School of Medicine, New York, NY 10016, USA michelle.krogsgaard@nyulangone.org (M.K.) – name: 1 Ronald O Perelman Department of Dermatology, NYU Grossman School of Medicine, New York, NY 10016, USA; miladadelmilad.ibrahim@nyulangone.org (M.I.); irineu.illabochaca@nyulangone.org (I.I.-B.); eleazar.vega-saenzdemiera@nyulangone.org (E.V.-S.d.M.) |
| Author_xml | – sequence: 1 givenname: Milad orcidid: 0000-0001-8841-7393 surname: Ibrahim fullname: Ibrahim, Milad organization: Ronald O Perelman Department of Dermatology, NYU Grossman School of Medicine, New York, NY 10016, USA – sequence: 2 givenname: Irineu surname: Illa-Bochaca fullname: Illa-Bochaca, Irineu organization: Ronald O Perelman Department of Dermatology, NYU Grossman School of Medicine, New York, NY 10016, USA – sequence: 3 givenname: Faisal orcidid: 0000-0002-9034-4100 surname: Fa'ak fullname: Fa'ak, Faisal organization: Ronald O Perelman Department of Dermatology, NYU Grossman School of Medicine, New York, NY 10016, USA – sequence: 4 givenname: Kelsey R orcidid: 0000-0003-1093-8628 surname: Monson fullname: Monson, Kelsey R organization: Department of Population Health, NYU Grossman School of Medicine, New York, NY 10016, USA – sequence: 5 givenname: Robert surname: Ferguson fullname: Ferguson, Robert organization: Department of Population Health, NYU Grossman School of Medicine, New York, NY 10016, USA – sequence: 6 givenname: Chen surname: Lyu fullname: Lyu, Chen organization: Department of Population Health, NYU Grossman School of Medicine, New York, NY 10016, USA – sequence: 7 givenname: Eleazar surname: Vega-Saenz de Miera fullname: Vega-Saenz de Miera, Eleazar organization: Ronald O Perelman Department of Dermatology, NYU Grossman School of Medicine, New York, NY 10016, USA – sequence: 8 givenname: Paul surname: Johannet fullname: Johannet, Paul organization: Ronald O Perelman Department of Dermatology, NYU Grossman School of Medicine, New York, NY 10016, USA – sequence: 9 givenname: Margaret surname: Chou fullname: Chou, Margaret organization: Ronald O Perelman Department of Dermatology, NYU Grossman School of Medicine, New York, NY 10016, USA – sequence: 10 givenname: Justin surname: Mastroianni fullname: Mastroianni, Justin organization: Department of Pathology, NYU Grossman School of Medicine, New York, NY 10016, USA – sequence: 11 givenname: Farbod surname: Darvishian fullname: Darvishian, Farbod organization: Department of Pathology, NYU Grossman School of Medicine, New York, NY 10016, USA – sequence: 12 givenname: Tomas surname: Kirchhoff fullname: Kirchhoff, Tomas organization: Interdisciplinary Melanoma Cooperative Group, NYU Langone Health, 522 First Ave, New York, NY 10016, USA – sequence: 13 givenname: Judy surname: Zhong fullname: Zhong, Judy organization: Interdisciplinary Melanoma Cooperative Group, NYU Langone Health, 522 First Ave, New York, NY 10016, USA – sequence: 14 givenname: Michelle orcidid: 0000-0001-5006-7981 surname: Krogsgaard fullname: Krogsgaard, Michelle organization: Interdisciplinary Melanoma Cooperative Group, NYU Langone Health, 522 First Ave, New York, NY 10016, USA – sequence: 15 givenname: Iman surname: Osman fullname: Osman, Iman organization: Interdisciplinary Melanoma Cooperative Group, NYU Langone Health, 522 First Ave, New York, NY 10016, USA |
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| Keywords | KDR targeted therapy melanoma germline immune response |
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| Snippet | We previously reported a higher incidence of a pathogenic germline variant in the kinase insert domain receptor (KDR) in melanoma patients compared to the... Background: We previously reported a higher incidence of a pathogenic germline variant in the kinase insert domain receptor (KDR) in melanoma patients compared... Despite the improvement in melanoma treatment over the last decade, there is still a need for developing new treatment strategies that can achieve complete and... Simple SummaryDespite the improvement in melanoma treatment over the last decade, there is still a need for developing new treatment strategies that can... BACKGROUNDWe previously reported a higher incidence of a pathogenic germline variant in the kinase insert domain receptor (KDR) in melanoma patients compared... |
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| SubjectTerms | 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 |
| Title | Kinase Insert Domain Receptor Q472H Pathogenic Germline Variant Impacts Melanoma Tumor Growth and Patient Treatment Outcomes |
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