Natural killer cells are essential for the ability of BRAF inhibitors to control BRAFV600E-mutant metastatic melanoma.
Identifieur interne : 003692 ( Main/Exploration ); précédent : 003691; suivant : 003693Natural killer cells are essential for the ability of BRAF inhibitors to control BRAFV600E-mutant metastatic melanoma.
Auteurs : Lucas Ferrari De Andrade [Australie] ; Shin F. Ngiow [Australie] ; Kimberley Stannard [Australie] ; Sylvie Rusakiewicz [France] ; Murugan Kalimutho [Australie] ; Kum Kum Khanna [Australie] ; Siok-Keen Tey [Australie] ; Kazuyoshi Takeda [Japon] ; Laurence Zitvogel [France] ; Ludovic Martinet [Australie] ; Mark J. Smyth [Australie]Source :
- Cancer research [ 1538-7445 ] ; 2014.
Descripteurs français
- KwdFr :
- Animaux, Cellules tueuses naturelles (anatomopathologie), Cellules tueuses naturelles (métabolisme), Humains, Immunothérapie, Lignée cellulaire tumorale, Mutation, Mélanome (), Mélanome (anatomopathologie), Mélanome (génétique), Mélanome (immunologie), Métastase tumorale (anatomopathologie), Métastase tumorale (génétique), Métastase tumorale (immunologie), Prolifération cellulaire (génétique), Protéines proto-oncogènes B-raf (antagonistes et inhibiteurs), Protéines proto-oncogènes B-raf (génétique), Résistance aux médicaments antinéoplasiques (génétique), Résistance aux médicaments antinéoplasiques (immunologie), Souris, Transduction du signal (génétique).
- MESH :
- anatomopathologie : Cellules tueuses naturelles, Mélanome, Métastase tumorale.
- antagonistes et inhibiteurs : Protéines proto-oncogènes B-raf.
- génétique : Mélanome, Métastase tumorale, Prolifération cellulaire, Protéines proto-oncogènes B-raf, Résistance aux médicaments antinéoplasiques, Transduction du signal.
- immunologie : Mélanome, Métastase tumorale, Résistance aux médicaments antinéoplasiques.
- métabolisme : Cellules tueuses naturelles.
- Animaux, Humains, Immunothérapie, Lignée cellulaire tumorale, Mutation, Mélanome, Souris.
English descriptors
- KwdEn :
- Animals, Cell Line, Tumor, Cell Proliferation (genetics), Drug Resistance, Neoplasm (genetics), Drug Resistance, Neoplasm (immunology), Humans, Immunotherapy, Killer Cells, Natural (metabolism), Killer Cells, Natural (pathology), Melanoma (genetics), Melanoma (immunology), Melanoma (pathology), Melanoma (therapy), Mice, Mutation, Neoplasm Metastasis (genetics), Neoplasm Metastasis (immunology), Neoplasm Metastasis (pathology), Proto-Oncogene Proteins B-raf (antagonists & inhibitors), Proto-Oncogene Proteins B-raf (genetics), Signal Transduction (genetics).
- MESH :
- chemical , antagonists & inhibitors : Proto-Oncogene Proteins B-raf.
- genetics : Cell Proliferation, Drug Resistance, Neoplasm, Melanoma, Neoplasm Metastasis, Proto-Oncogene Proteins B-raf, Signal Transduction.
- immunology : Drug Resistance, Neoplasm, Melanoma, Neoplasm Metastasis.
- metabolism : Killer Cells, Natural.
- pathology : Killer Cells, Natural, Melanoma, Neoplasm Metastasis.
- therapy : Melanoma.
- Animals, Cell Line, Tumor, Humans, Immunotherapy, Mice, Mutation.
Abstract
BRAF(V600E) is a major oncogenic mutation found in approximately 50% of human melanoma that confers constitutive activation of the MAPK pathway and increased melanoma growth. Inhibition of BRAF(V600E) by oncogene targeting therapy increases overall survival of patients with melanoma, but is unable to produce many durable responses. Adaptive drug resistance remains the main limitation to BRAF(V600E) inhibitor clinical efficacy and immune-based strategies could be useful to overcome disease relapse. Tumor microenvironment greatly differs between visceral metastasis and primary cutaneous melanoma, and the mechanisms involved in the antimetastatic efficacy of BRAF(V600E) inhibitors remain to be determined. To address this question, we developed a metastatic BRAF(V600E)-mutant melanoma cell line and demonstrated that the antimetastatic properties of BRAF inhibitor PLX4720 (a research analogue of vemurafenib) require host natural killer (NK) cells and perforin. Indeed, PLX4720 not only directly limited BRAF(V600E)-induced tumor cell proliferation, but also affected NK cell functions. We showed that PLX4720 increases the phosphorylation of ERK1/2, CD69 expression, and proliferation of mouse NK cells in vitro. NK cell frequencies were significantly enhanced by PLX4720 specifically in the lungs of mice with BRAF(V600E) lung metastases. Furthermore, PLX4720 also increased human NK cell pERK1/2, CD69 expression, and IFNγ release in the context of anti-NKp30 and IL2 stimulation. Overall, this study supports the idea that additional NK cell-based immunotherapy (by checkpoint blockade or agonists or cytokines) may combine well with BRAF(V600E) inhibitor therapy to promote more durable responses in melanoma.
DOI: 10.1158/0008-5472.CAN-14-1339
PubMed: 25351955
Affiliations:
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INSERM U1015, Villejuif, France. Center of Clinical Investigations in Biotherapies of Cancer (CICBT) 1428, Villejuif, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Gustave Roussy Cancer Campus, Villejuif, France. INSERM U1015, Villejuif, France. Center of Clinical Investigations in Biotherapies of Cancer (CICBT) 1428, Villejuif</wicri:regionArea><wicri:noRegion>Villejuif</wicri:noRegion><wicri:noRegion>Villejuif</wicri:noRegion></affiliation></author><author><name sortKey="Kalimutho, Murugan" sort="Kalimutho, Murugan" uniqKey="Kalimutho M" first="Murugan" last="Kalimutho">Murugan Kalimutho</name><affiliation wicri:level="1"><nlm:affiliation>Signal Transduction Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Signal Transduction Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland</wicri:regionArea><wicri:noRegion>Queensland</wicri:noRegion></affiliation></author><author><name sortKey="Khanna, Kum Kum" sort="Khanna, Kum Kum" uniqKey="Khanna K" first="Kum Kum" last="Khanna">Kum Kum Khanna</name><affiliation wicri:level="1"><nlm:affiliation>Signal Transduction Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Signal Transduction Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland</wicri:regionArea><wicri:noRegion>Queensland</wicri:noRegion></affiliation></author><author><name sortKey="Tey, Siok Keen" sort="Tey, Siok Keen" uniqKey="Tey S" first="Siok-Keen" last="Tey">Siok-Keen Tey</name><affiliation wicri:level="1"><nlm:affiliation>Bone Marrow Transplant Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Bone Marrow Transplant Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland</wicri:regionArea><wicri:noRegion>Queensland</wicri:noRegion></affiliation></author><author><name sortKey="Takeda, Kazuyoshi" sort="Takeda, Kazuyoshi" uniqKey="Takeda K" first="Kazuyoshi" last="Takeda">Kazuyoshi Takeda</name><affiliation wicri:level="3"><nlm:affiliation>Department of Immunology, Juntendo University School of Medicine, Hongo, Bunkyo-ku, Tokyo, Japan.</nlm:affiliation><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Immunology, Juntendo University School of Medicine, Hongo, Bunkyo-ku, Tokyo</wicri:regionArea><placeName><settlement type="city">Tokyo</settlement><region type="région">Région de Kantō</region></placeName></affiliation></author><author><name sortKey="Zitvogel, Laurence" sort="Zitvogel, Laurence" uniqKey="Zitvogel L" first="Laurence" last="Zitvogel">Laurence Zitvogel</name><affiliation wicri:level="1"><nlm:affiliation>Gustave Roussy Cancer Campus, Villejuif, France. INSERM U1015, Villejuif, France. Université Paris Sud-XI, Faculté de Médecine, Le Kremlin Bicêtre, France. Department of Medical Oncology, IGR, Villejuif, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Gustave Roussy Cancer Campus, Villejuif, France. INSERM U1015, Villejuif, France. Université Paris Sud-XI, Faculté de Médecine, Le Kremlin Bicêtre, France. Department of Medical Oncology, IGR, Villejuif</wicri:regionArea><wicri:noRegion>Villejuif</wicri:noRegion><wicri:noRegion>Villejuif</wicri:noRegion></affiliation></author><author><name sortKey="Martinet, Ludovic" sort="Martinet, Ludovic" uniqKey="Martinet L" first="Ludovic" last="Martinet">Ludovic Martinet</name><affiliation wicri:level="1"><nlm:affiliation>Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland</wicri:regionArea><wicri:noRegion>Queensland</wicri:noRegion></affiliation></author><author><name sortKey="Smyth, Mark J" sort="Smyth, Mark J" uniqKey="Smyth M" first="Mark J" last="Smyth">Mark J. Smyth</name><affiliation wicri:level="1"><nlm:affiliation>Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia. School of Medicine, University of Queensland, Herston, Queensland, Australia. mark.smyth@qimrberghofer.edu.au.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia. 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Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Laboratorio de Pesquisa em Células Inflamatórias e Neoplásicas Group, Universidade Federal do Paraná, Curitiba, Paraná, Brazil. Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland</wicri:regionArea><wicri:noRegion>Queensland</wicri:noRegion></affiliation></author><author><name sortKey="Ngiow, Shin F" sort="Ngiow, Shin F" uniqKey="Ngiow S" first="Shin F" last="Ngiow">Shin F. Ngiow</name><affiliation wicri:level="1"><nlm:affiliation>Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland</wicri:regionArea><wicri:noRegion>Queensland</wicri:noRegion></affiliation></author><author><name sortKey="Stannard, Kimberley" sort="Stannard, Kimberley" uniqKey="Stannard K" first="Kimberley" last="Stannard">Kimberley Stannard</name><affiliation wicri:level="1"><nlm:affiliation>Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland</wicri:regionArea><wicri:noRegion>Queensland</wicri:noRegion></affiliation></author><author><name sortKey="Rusakiewicz, Sylvie" sort="Rusakiewicz, Sylvie" uniqKey="Rusakiewicz S" first="Sylvie" last="Rusakiewicz">Sylvie Rusakiewicz</name><affiliation wicri:level="1"><nlm:affiliation>Gustave Roussy Cancer Campus, Villejuif, France. INSERM U1015, Villejuif, France. Center of Clinical Investigations in Biotherapies of Cancer (CICBT) 1428, Villejuif, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Gustave Roussy Cancer Campus, Villejuif, France. INSERM U1015, Villejuif, France. Center of Clinical Investigations in Biotherapies of Cancer (CICBT) 1428, Villejuif</wicri:regionArea><wicri:noRegion>Villejuif</wicri:noRegion><wicri:noRegion>Villejuif</wicri:noRegion></affiliation></author><author><name sortKey="Kalimutho, Murugan" sort="Kalimutho, Murugan" uniqKey="Kalimutho M" first="Murugan" last="Kalimutho">Murugan Kalimutho</name><affiliation wicri:level="1"><nlm:affiliation>Signal Transduction Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Signal Transduction Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland</wicri:regionArea><wicri:noRegion>Queensland</wicri:noRegion></affiliation></author><author><name sortKey="Khanna, Kum Kum" sort="Khanna, Kum Kum" uniqKey="Khanna K" first="Kum Kum" last="Khanna">Kum Kum Khanna</name><affiliation wicri:level="1"><nlm:affiliation>Signal Transduction Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Signal Transduction Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland</wicri:regionArea><wicri:noRegion>Queensland</wicri:noRegion></affiliation></author><author><name sortKey="Tey, Siok Keen" sort="Tey, Siok Keen" uniqKey="Tey S" first="Siok-Keen" last="Tey">Siok-Keen Tey</name><affiliation wicri:level="1"><nlm:affiliation>Bone Marrow Transplant Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Bone Marrow Transplant Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland</wicri:regionArea><wicri:noRegion>Queensland</wicri:noRegion></affiliation></author><author><name sortKey="Takeda, Kazuyoshi" sort="Takeda, Kazuyoshi" uniqKey="Takeda K" first="Kazuyoshi" last="Takeda">Kazuyoshi Takeda</name><affiliation wicri:level="3"><nlm:affiliation>Department of Immunology, Juntendo University School of Medicine, Hongo, Bunkyo-ku, Tokyo, Japan.</nlm:affiliation><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Immunology, Juntendo University School of Medicine, Hongo, Bunkyo-ku, Tokyo</wicri:regionArea><placeName><settlement type="city">Tokyo</settlement><region type="région">Région de Kantō</region></placeName></affiliation></author><author><name sortKey="Zitvogel, Laurence" sort="Zitvogel, Laurence" uniqKey="Zitvogel L" first="Laurence" last="Zitvogel">Laurence Zitvogel</name><affiliation wicri:level="1"><nlm:affiliation>Gustave Roussy Cancer Campus, Villejuif, France. INSERM U1015, Villejuif, France. Université Paris Sud-XI, Faculté de Médecine, Le Kremlin Bicêtre, France. Department of Medical Oncology, IGR, Villejuif, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Gustave Roussy Cancer Campus, Villejuif, France. INSERM U1015, Villejuif, France. Université Paris Sud-XI, Faculté de Médecine, Le Kremlin Bicêtre, France. Department of Medical Oncology, IGR, Villejuif</wicri:regionArea><wicri:noRegion>Villejuif</wicri:noRegion><wicri:noRegion>Villejuif</wicri:noRegion></affiliation></author><author><name sortKey="Martinet, Ludovic" sort="Martinet, Ludovic" uniqKey="Martinet L" first="Ludovic" last="Martinet">Ludovic Martinet</name><affiliation wicri:level="1"><nlm:affiliation>Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland</wicri:regionArea><wicri:noRegion>Queensland</wicri:noRegion></affiliation></author><author><name sortKey="Smyth, Mark J" sort="Smyth, Mark J" uniqKey="Smyth M" first="Mark J" last="Smyth">Mark J. Smyth</name><affiliation wicri:level="1"><nlm:affiliation>Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia. School of Medicine, University of Queensland, Herston, Queensland, Australia. mark.smyth@qimrberghofer.edu.au.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia. School of Medicine, University of Queensland, Herston, Queensland</wicri:regionArea><wicri:noRegion>Queensland</wicri:noRegion></affiliation></author></analytic><series><title level="j">Cancer research</title><idno type="eISSN">1538-7445</idno><imprint><date when="2014" type="published">2014</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals</term><term>Cell Line, Tumor</term><term>Cell Proliferation (genetics)</term><term>Drug Resistance, Neoplasm (genetics)</term><term>Drug Resistance, Neoplasm (immunology)</term><term>Humans</term><term>Immunotherapy</term><term>Killer Cells, Natural (metabolism)</term><term>Killer Cells, Natural (pathology)</term><term>Melanoma (genetics)</term><term>Melanoma (immunology)</term><term>Melanoma (pathology)</term><term>Melanoma (therapy)</term><term>Mice</term><term>Mutation</term><term>Neoplasm Metastasis (genetics)</term><term>Neoplasm Metastasis (immunology)</term><term>Neoplasm Metastasis (pathology)</term><term>Proto-Oncogene Proteins B-raf (antagonists & inhibitors)</term><term>Proto-Oncogene Proteins B-raf (genetics)</term><term>Signal Transduction (genetics)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Animaux</term><term>Cellules tueuses naturelles (anatomopathologie)</term><term>Cellules tueuses naturelles (métabolisme)</term><term>Humains</term><term>Immunothérapie</term><term>Lignée cellulaire tumorale</term><term>Mutation</term><term>Mélanome ()</term><term>Mélanome (anatomopathologie)</term><term>Mélanome (génétique)</term><term>Mélanome (immunologie)</term><term>Métastase tumorale (anatomopathologie)</term><term>Métastase tumorale (génétique)</term><term>Métastase tumorale (immunologie)</term><term>Prolifération cellulaire (génétique)</term><term>Protéines proto-oncogènes B-raf (antagonistes et inhibiteurs)</term><term>Protéines proto-oncogènes B-raf (génétique)</term><term>Résistance aux médicaments antinéoplasiques (génétique)</term><term>Résistance aux médicaments antinéoplasiques (immunologie)</term><term>Souris</term><term>Transduction du signal (génétique)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="antagonists & inhibitors" xml:lang="en"><term>Proto-Oncogene Proteins B-raf</term></keywords><keywords scheme="MESH" qualifier="anatomopathologie" xml:lang="fr"><term>Cellules tueuses naturelles</term><term>Mélanome</term><term>Métastase tumorale</term></keywords><keywords scheme="MESH" qualifier="antagonistes et inhibiteurs" xml:lang="fr"><term>Protéines proto-oncogènes B-raf</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Cell Proliferation</term><term>Drug Resistance, Neoplasm</term><term>Melanoma</term><term>Neoplasm Metastasis</term><term>Proto-Oncogene Proteins B-raf</term><term>Signal Transduction</term></keywords><keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Mélanome</term><term>Métastase tumorale</term><term>Prolifération cellulaire</term><term>Protéines proto-oncogènes B-raf</term><term>Résistance aux médicaments antinéoplasiques</term><term>Transduction du signal</term></keywords><keywords scheme="MESH" qualifier="immunologie" xml:lang="fr"><term>Mélanome</term><term>Métastase tumorale</term><term>Résistance aux médicaments antinéoplasiques</term></keywords><keywords scheme="MESH" qualifier="immunology" xml:lang="en"><term>Drug Resistance, Neoplasm</term><term>Melanoma</term><term>Neoplasm Metastasis</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Killer Cells, Natural</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Cellules tueuses naturelles</term></keywords><keywords scheme="MESH" qualifier="pathology" xml:lang="en"><term>Killer Cells, Natural</term><term>Melanoma</term><term>Neoplasm Metastasis</term></keywords><keywords scheme="MESH" qualifier="therapy" xml:lang="en"><term>Melanoma</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Cell Line, Tumor</term><term>Humans</term><term>Immunotherapy</term><term>Mice</term><term>Mutation</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Animaux</term><term>Humains</term><term>Immunothérapie</term><term>Lignée cellulaire tumorale</term><term>Mutation</term><term>Mélanome</term><term>Souris</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">BRAF(V600E) is a major oncogenic mutation found in approximately 50% of human melanoma that confers constitutive activation of the MAPK pathway and increased melanoma growth. Inhibition of BRAF(V600E) by oncogene targeting therapy increases overall survival of patients with melanoma, but is unable to produce many durable responses. Adaptive drug resistance remains the main limitation to BRAF(V600E) inhibitor clinical efficacy and immune-based strategies could be useful to overcome disease relapse. Tumor microenvironment greatly differs between visceral metastasis and primary cutaneous melanoma, and the mechanisms involved in the antimetastatic efficacy of BRAF(V600E) inhibitors remain to be determined. To address this question, we developed a metastatic BRAF(V600E)-mutant melanoma cell line and demonstrated that the antimetastatic properties of BRAF inhibitor PLX4720 (a research analogue of vemurafenib) require host natural killer (NK) cells and perforin. Indeed, PLX4720 not only directly limited BRAF(V600E)-induced tumor cell proliferation, but also affected NK cell functions. We showed that PLX4720 increases the phosphorylation of ERK1/2, CD69 expression, and proliferation of mouse NK cells in vitro. NK cell frequencies were significantly enhanced by PLX4720 specifically in the lungs of mice with BRAF(V600E) lung metastases. Furthermore, PLX4720 also increased human NK cell pERK1/2, CD69 expression, and IFNγ release in the context of anti-NKp30 and IL2 stimulation. Overall, this study supports the idea that additional NK cell-based immunotherapy (by checkpoint blockade or agonists or cytokines) may combine well with BRAF(V600E) inhibitor therapy to promote more durable responses in melanoma.</div></front></TEI><affiliations><list><country><li>Australie</li><li>France</li><li>Japon</li></country><region><li>Région de Kantō</li></region><settlement><li>Tokyo</li></settlement></list><tree><country name="Australie"><noRegion><name sortKey="Ferrari De Andrade, Lucas" sort="Ferrari De Andrade, Lucas" uniqKey="Ferrari De Andrade L" first="Lucas" last="Ferrari De Andrade">Lucas Ferrari De Andrade</name></noRegion><name sortKey="Kalimutho, Murugan" sort="Kalimutho, Murugan" uniqKey="Kalimutho M" first="Murugan" last="Kalimutho">Murugan Kalimutho</name><name sortKey="Khanna, Kum Kum" sort="Khanna, Kum Kum" uniqKey="Khanna K" first="Kum Kum" last="Khanna">Kum Kum Khanna</name><name sortKey="Martinet, Ludovic" sort="Martinet, Ludovic" uniqKey="Martinet L" first="Ludovic" last="Martinet">Ludovic Martinet</name><name sortKey="Ngiow, Shin F" sort="Ngiow, Shin F" uniqKey="Ngiow S" first="Shin F" last="Ngiow">Shin F. Ngiow</name><name sortKey="Smyth, Mark J" sort="Smyth, Mark J" uniqKey="Smyth M" first="Mark J" last="Smyth">Mark J. Smyth</name><name sortKey="Stannard, Kimberley" sort="Stannard, Kimberley" uniqKey="Stannard K" first="Kimberley" last="Stannard">Kimberley Stannard</name><name sortKey="Tey, Siok Keen" sort="Tey, Siok Keen" uniqKey="Tey S" first="Siok-Keen" last="Tey">Siok-Keen Tey</name></country><country name="France"><noRegion><name sortKey="Rusakiewicz, Sylvie" sort="Rusakiewicz, Sylvie" uniqKey="Rusakiewicz S" first="Sylvie" last="Rusakiewicz">Sylvie Rusakiewicz</name></noRegion><name sortKey="Zitvogel, Laurence" sort="Zitvogel, Laurence" uniqKey="Zitvogel L" first="Laurence" last="Zitvogel">Laurence Zitvogel</name></country><country name="Japon"><region name="Région de Kantō"><name sortKey="Takeda, Kazuyoshi" sort="Takeda, Kazuyoshi" uniqKey="Takeda K" first="Kazuyoshi" last="Takeda">Kazuyoshi Takeda</name></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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