Pan-erbB inhibition potentiates BRAF inhibitors for melanoma treatment.
Identifieur interne : 001D74 ( PubMed/Checkpoint ); précédent : 001D73; suivant : 001D75Pan-erbB inhibition potentiates BRAF inhibitors for melanoma treatment.
Auteurs : Yuen-Keng Ng [États-Unis] ; Jia-Ying Lee ; Kathryn M. Supko ; Ayesha Khan ; Salina M. Torres ; Marianne Berwick ; Jonhan Ho ; John M. Kirkwood ; Jill M. Siegfried ; Laura P. StabileSource :
- Melanoma research [ 1473-5636 ] ; 2014.
Descripteurs français
- KwdFr :
- Apoptose (), Concentration inhibitrice 50, Humains, Indoles (pharmacologie), Inhibiteurs de protéines kinases (pharmacologie), Ligands, Lignée cellulaire tumorale, Morpholines (pharmacologie), Mutation, Mélanome (anatomopathologie), Mélanome (enzymologie), Mélanome (génétique), Points de contrôle de la phase G1 du cycle cellulaire (), Prolifération cellulaire (), Protocoles de polychimiothérapie antinéoplasique (pharmacologie), Protéines proto-oncogènes B-raf (antagonistes et inhibiteurs), Protéines proto-oncogènes B-raf (génétique), Protéines proto-oncogènes B-raf (métabolisme), Relation dose-effet des médicaments, Récepteurs ErbB (antagonistes et inhibiteurs), Récepteurs ErbB (métabolisme), Sulfonamides (pharmacologie), Thérapie moléculaire ciblée, Transduction du signal (), Tumeurs cutanées (anatomopathologie), Tumeurs cutanées (enzymologie), Tumeurs cutanées (génétique).
- MESH :
- anatomopathologie : Mélanome, Tumeurs cutanées.
- antagonistes et inhibiteurs : Protéines proto-oncogènes B-raf, Récepteurs ErbB.
- enzymologie : Mélanome, Tumeurs cutanées.
- génétique : Mélanome, Protéines proto-oncogènes B-raf, Tumeurs cutanées.
- métabolisme : Protéines proto-oncogènes B-raf, Récepteurs ErbB.
- pharmacologie : Indoles, Inhibiteurs de protéines kinases, Morpholines, Protocoles de polychimiothérapie antinéoplasique, Sulfonamides.
- Apoptose, Concentration inhibitrice 50, Humains, Ligands, Lignée cellulaire tumorale, Mutation, Points de contrôle de la phase G1 du cycle cellulaire, Prolifération cellulaire, Relation dose-effet des médicaments, Thérapie moléculaire ciblée, Transduction du signal.
English descriptors
- KwdEn :
- Antineoplastic Combined Chemotherapy Protocols (pharmacology), Apoptosis (drug effects), Cell Line, Tumor, Cell Proliferation (drug effects), Dose-Response Relationship, Drug, ErbB Receptors (antagonists & inhibitors), ErbB Receptors (metabolism), G1 Phase Cell Cycle Checkpoints (drug effects), Humans, Indoles (pharmacology), Inhibitory Concentration 50, Ligands, Melanoma (enzymology), Melanoma (genetics), Melanoma (pathology), Molecular Targeted Therapy, Morpholines (pharmacology), Mutation, Protein Kinase Inhibitors (pharmacology), Proto-Oncogene Proteins B-raf (antagonists & inhibitors), Proto-Oncogene Proteins B-raf (genetics), Proto-Oncogene Proteins B-raf (metabolism), Signal Transduction (drug effects), Skin Neoplasms (enzymology), Skin Neoplasms (genetics), Skin Neoplasms (pathology), Sulfonamides (pharmacology).
- MESH :
- chemical , antagonists & inhibitors : ErbB Receptors, Proto-Oncogene Proteins B-raf.
- drug effects : Apoptosis, Cell Proliferation, G1 Phase Cell Cycle Checkpoints, Signal Transduction.
- enzymology : Melanoma, Skin Neoplasms.
- genetics : Melanoma, Proto-Oncogene Proteins B-raf, Skin Neoplasms.
- chemical , metabolism : ErbB Receptors, Proto-Oncogene Proteins B-raf.
- pathology : Melanoma, Skin Neoplasms.
- pharmacology : Antineoplastic Combined Chemotherapy Protocols, Indoles, Morpholines, Protein Kinase Inhibitors, Sulfonamides.
- Cell Line, Tumor, Dose-Response Relationship, Drug, Humans, Inhibitory Concentration 50, Ligands, Molecular Targeted Therapy, Mutation.
Abstract
The BRAF inhibitor vemurafenib is currently used for treating patients with BRAF V600E mutant melanoma. However, the responses to vemurafenib are generally partial and of relatively short duration. Recent evidence suggests that activation of the epidermal growth factor receptor (EGFR)/erbB signaling pathway may be responsible for the development of BRAF inhibitor resistance in melanoma patients. In this study, we characterized the erbB family of receptors and ligands in melanoma cell lines and examined whether targeting both BRAF and erbB provided enhanced antitumor activity in BRAF mutant melanoma. Variable levels of erbB2, erbB3, and truncated erbB4 were expressed in both BRAF wildtype and mutant melanoma cells with no significant differences between wildtype and mutant lines. EGFR was rarely expressed. Neuregulin 3 and neuregulin 4 were the major erbB ligands released by melanoma cells. Multi-erbB targeting with the irreversible tyrosine kinase inhibitor canertinib exerted a more effective growth inhibitory effect in both BRAF wildtype and mutant melanoma cells compared with the single-erbB or dual-erbB targeting inhibitors, gefitinib, erlotinib, and lapatinib. Canertinib inhibited both EGF-induced and neuregulin 1-induced erbB downstream signaling in both mutant and wildtype cell lines. However, canertinib induced apoptosis and sub-G1 arrest only in mutant cells. Canertinib statistically increased the antiproliferative effects of vemurafenib in the BRAF mutant melanoma cell lines while little or no enhanced effect was observed with the combination treatment in the wildtype cell lines. A combined inhibition strategy targeting BRAF together with multiple erbB family kinases is potentially beneficial for treating BRAF V600E mutant melanoma. Wildtype BRAF melanoma may also benefit from a multi-erbB kinase inhibitor.
DOI: 10.1097/CMR.0000000000000060
PubMed: 24709886
Affiliations:
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pubmed:24709886Le document en format XML
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<term>Apoptosis (drug effects)</term>
<term>Cell Line, Tumor</term>
<term>Cell Proliferation (drug effects)</term>
<term>Dose-Response Relationship, Drug</term>
<term>ErbB Receptors (antagonists & inhibitors)</term>
<term>ErbB Receptors (metabolism)</term>
<term>G1 Phase Cell Cycle Checkpoints (drug effects)</term>
<term>Humans</term>
<term>Indoles (pharmacology)</term>
<term>Inhibitory Concentration 50</term>
<term>Ligands</term>
<term>Melanoma (enzymology)</term>
<term>Melanoma (genetics)</term>
<term>Melanoma (pathology)</term>
<term>Molecular Targeted Therapy</term>
<term>Morpholines (pharmacology)</term>
<term>Mutation</term>
<term>Protein Kinase Inhibitors (pharmacology)</term>
<term>Proto-Oncogene Proteins B-raf (antagonists & inhibitors)</term>
<term>Proto-Oncogene Proteins B-raf (genetics)</term>
<term>Proto-Oncogene Proteins B-raf (metabolism)</term>
<term>Signal Transduction (drug effects)</term>
<term>Skin Neoplasms (enzymology)</term>
<term>Skin Neoplasms (genetics)</term>
<term>Skin Neoplasms (pathology)</term>
<term>Sulfonamides (pharmacology)</term>
</keywords>
<keywords scheme="KwdFr" xml:lang="fr"><term>Apoptose ()</term>
<term>Concentration inhibitrice 50</term>
<term>Humains</term>
<term>Indoles (pharmacologie)</term>
<term>Inhibiteurs de protéines kinases (pharmacologie)</term>
<term>Ligands</term>
<term>Lignée cellulaire tumorale</term>
<term>Morpholines (pharmacologie)</term>
<term>Mutation</term>
<term>Mélanome (anatomopathologie)</term>
<term>Mélanome (enzymologie)</term>
<term>Mélanome (génétique)</term>
<term>Points de contrôle de la phase G1 du cycle cellulaire ()</term>
<term>Prolifération cellulaire ()</term>
<term>Protocoles de polychimiothérapie antinéoplasique (pharmacologie)</term>
<term>Protéines proto-oncogènes B-raf (antagonistes et inhibiteurs)</term>
<term>Protéines proto-oncogènes B-raf (génétique)</term>
<term>Protéines proto-oncogènes B-raf (métabolisme)</term>
<term>Relation dose-effet des médicaments</term>
<term>Récepteurs ErbB (antagonistes et inhibiteurs)</term>
<term>Récepteurs ErbB (métabolisme)</term>
<term>Sulfonamides (pharmacologie)</term>
<term>Thérapie moléculaire ciblée</term>
<term>Transduction du signal ()</term>
<term>Tumeurs cutanées (anatomopathologie)</term>
<term>Tumeurs cutanées (enzymologie)</term>
<term>Tumeurs cutanées (génétique)</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="antagonists & inhibitors" xml:lang="en"><term>ErbB Receptors</term>
<term>Proto-Oncogene Proteins B-raf</term>
</keywords>
<keywords scheme="MESH" qualifier="anatomopathologie" xml:lang="fr"><term>Mélanome</term>
<term>Tumeurs cutanées</term>
</keywords>
<keywords scheme="MESH" qualifier="antagonistes et inhibiteurs" xml:lang="fr"><term>Protéines proto-oncogènes B-raf</term>
<term>Récepteurs ErbB</term>
</keywords>
<keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Apoptosis</term>
<term>Cell Proliferation</term>
<term>G1 Phase Cell Cycle Checkpoints</term>
<term>Signal Transduction</term>
</keywords>
<keywords scheme="MESH" qualifier="enzymologie" xml:lang="fr"><term>Mélanome</term>
<term>Tumeurs cutanées</term>
</keywords>
<keywords scheme="MESH" qualifier="enzymology" xml:lang="en"><term>Melanoma</term>
<term>Skin Neoplasms</term>
</keywords>
<keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Melanoma</term>
<term>Proto-Oncogene Proteins B-raf</term>
<term>Skin Neoplasms</term>
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<keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Mélanome</term>
<term>Protéines proto-oncogènes B-raf</term>
<term>Tumeurs cutanées</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>ErbB Receptors</term>
<term>Proto-Oncogene Proteins B-raf</term>
</keywords>
<keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Protéines proto-oncogènes B-raf</term>
<term>Récepteurs ErbB</term>
</keywords>
<keywords scheme="MESH" qualifier="pathology" xml:lang="en"><term>Melanoma</term>
<term>Skin Neoplasms</term>
</keywords>
<keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Indoles</term>
<term>Inhibiteurs de protéines kinases</term>
<term>Morpholines</term>
<term>Protocoles de polychimiothérapie antinéoplasique</term>
<term>Sulfonamides</term>
</keywords>
<keywords scheme="MESH" qualifier="pharmacology" xml:lang="en"><term>Antineoplastic Combined Chemotherapy Protocols</term>
<term>Indoles</term>
<term>Morpholines</term>
<term>Protein Kinase Inhibitors</term>
<term>Sulfonamides</term>
</keywords>
<keywords scheme="MESH" xml:lang="en"><term>Cell Line, Tumor</term>
<term>Dose-Response Relationship, Drug</term>
<term>Humans</term>
<term>Inhibitory Concentration 50</term>
<term>Ligands</term>
<term>Molecular Targeted Therapy</term>
<term>Mutation</term>
</keywords>
<keywords scheme="MESH" xml:lang="fr"><term>Apoptose</term>
<term>Concentration inhibitrice 50</term>
<term>Humains</term>
<term>Ligands</term>
<term>Lignée cellulaire tumorale</term>
<term>Mutation</term>
<term>Points de contrôle de la phase G1 du cycle cellulaire</term>
<term>Prolifération cellulaire</term>
<term>Relation dose-effet des médicaments</term>
<term>Thérapie moléculaire ciblée</term>
<term>Transduction du signal</term>
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<front><div type="abstract" xml:lang="en">The BRAF inhibitor vemurafenib is currently used for treating patients with BRAF V600E mutant melanoma. However, the responses to vemurafenib are generally partial and of relatively short duration. Recent evidence suggests that activation of the epidermal growth factor receptor (EGFR)/erbB signaling pathway may be responsible for the development of BRAF inhibitor resistance in melanoma patients. In this study, we characterized the erbB family of receptors and ligands in melanoma cell lines and examined whether targeting both BRAF and erbB provided enhanced antitumor activity in BRAF mutant melanoma. Variable levels of erbB2, erbB3, and truncated erbB4 were expressed in both BRAF wildtype and mutant melanoma cells with no significant differences between wildtype and mutant lines. EGFR was rarely expressed. Neuregulin 3 and neuregulin 4 were the major erbB ligands released by melanoma cells. Multi-erbB targeting with the irreversible tyrosine kinase inhibitor canertinib exerted a more effective growth inhibitory effect in both BRAF wildtype and mutant melanoma cells compared with the single-erbB or dual-erbB targeting inhibitors, gefitinib, erlotinib, and lapatinib. Canertinib inhibited both EGF-induced and neuregulin 1-induced erbB downstream signaling in both mutant and wildtype cell lines. However, canertinib induced apoptosis and sub-G1 arrest only in mutant cells. Canertinib statistically increased the antiproliferative effects of vemurafenib in the BRAF mutant melanoma cell lines while little or no enhanced effect was observed with the combination treatment in the wildtype cell lines. A combined inhibition strategy targeting BRAF together with multiple erbB family kinases is potentially beneficial for treating BRAF V600E mutant melanoma. Wildtype BRAF melanoma may also benefit from a multi-erbB kinase inhibitor.</div>
</front>
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<DateCreated><Year>2014</Year>
<Month>04</Month>
<Day>29</Day>
</DateCreated>
<DateCompleted><Year>2014</Year>
<Month>12</Month>
<Day>28</Day>
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<DateRevised><Year>2017</Year>
<Month>10</Month>
<Day>27</Day>
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<JournalIssue CitedMedium="Internet"><Volume>24</Volume>
<Issue>3</Issue>
<PubDate><Year>2014</Year>
<Month>Jun</Month>
</PubDate>
</JournalIssue>
<Title>Melanoma research</Title>
<ISOAbbreviation>Melanoma Res.</ISOAbbreviation>
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<ArticleTitle>Pan-erbB inhibition potentiates BRAF inhibitors for melanoma treatment.</ArticleTitle>
<Pagination><MedlinePgn>207-18</MedlinePgn>
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<ELocationID EIdType="doi" ValidYN="Y">10.1097/CMR.0000000000000060</ELocationID>
<Abstract><AbstractText>The BRAF inhibitor vemurafenib is currently used for treating patients with BRAF V600E mutant melanoma. However, the responses to vemurafenib are generally partial and of relatively short duration. Recent evidence suggests that activation of the epidermal growth factor receptor (EGFR)/erbB signaling pathway may be responsible for the development of BRAF inhibitor resistance in melanoma patients. In this study, we characterized the erbB family of receptors and ligands in melanoma cell lines and examined whether targeting both BRAF and erbB provided enhanced antitumor activity in BRAF mutant melanoma. Variable levels of erbB2, erbB3, and truncated erbB4 were expressed in both BRAF wildtype and mutant melanoma cells with no significant differences between wildtype and mutant lines. EGFR was rarely expressed. Neuregulin 3 and neuregulin 4 were the major erbB ligands released by melanoma cells. Multi-erbB targeting with the irreversible tyrosine kinase inhibitor canertinib exerted a more effective growth inhibitory effect in both BRAF wildtype and mutant melanoma cells compared with the single-erbB or dual-erbB targeting inhibitors, gefitinib, erlotinib, and lapatinib. Canertinib inhibited both EGF-induced and neuregulin 1-induced erbB downstream signaling in both mutant and wildtype cell lines. However, canertinib induced apoptosis and sub-G1 arrest only in mutant cells. Canertinib statistically increased the antiproliferative effects of vemurafenib in the BRAF mutant melanoma cell lines while little or no enhanced effect was observed with the combination treatment in the wildtype cell lines. A combined inhibition strategy targeting BRAF together with multiple erbB family kinases is potentially beneficial for treating BRAF V600E mutant melanoma. Wildtype BRAF melanoma may also benefit from a multi-erbB kinase inhibitor.</AbstractText>
</Abstract>
<AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Ng</LastName>
<ForeName>Yuen-Keng</ForeName>
<Initials>YK</Initials>
<AffiliationInfo><Affiliation>aDepartment of Pharmacology and Chemical Biology, University of Pittsburgh Cancer Institute Departments of bPathology cMedicine, University of Pittsburgh dDepartment of Dermatology, University of Pittsburgh Medical Center eDepartment of Biological Sciences, Carnegie Mellon University, Pittsburgh, Pennsylvania fDepartment of Internal Medicine, Division of Epidemiology and Biostatistics, University of New Mexico, Albuquerque, New Mexico gDepartment of Pharmacology, University of Minnesota, Minneapolis, Minnesota, USA.</Affiliation>
</AffiliationInfo>
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<Author ValidYN="Y"><LastName>Lee</LastName>
<ForeName>Jia-Ying</ForeName>
<Initials>JY</Initials>
</Author>
<Author ValidYN="Y"><LastName>Supko</LastName>
<ForeName>Kathryn M</ForeName>
<Initials>KM</Initials>
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<Author ValidYN="Y"><LastName>Khan</LastName>
<ForeName>Ayesha</ForeName>
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<ForeName>Salina M</ForeName>
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<ForeName>Marianne</ForeName>
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<Initials>JM</Initials>
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<Author ValidYN="Y"><LastName>Siegfried</LastName>
<ForeName>Jill M</ForeName>
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<Author ValidYN="Y"><LastName>Stabile</LastName>
<ForeName>Laura P</ForeName>
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