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Response and Resistance to Trametinib in MAP2K1-Mutant Triple-Negative Melanoma

The development of targeted therapies for non-BRAF p.Val600-mutant melanomas remains a challenge. Triple wildtype (TWT) melanomas that lack mutations in BRAF, NRAS, or NF1 form 10% of human melanomas and are heterogeneous in their genomic drivers. MAP2K1 mutations are enriched in BRAF-mutant melanom...

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Autores principales: Krebs, Fanny Seraphine, Moura, Bianca, Missiaglia, Edoardo, Aedo-Lopez, Veronica, Michielin, Olivier, Tsantoulis, Petros, Bisig, Bettina, Trimech, Mounir, Zoete, Vincent, Homicsko, Krisztian
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10003177/
https://www.ncbi.nlm.nih.gov/pubmed/36901951
http://dx.doi.org/10.3390/ijms24054520
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author Krebs, Fanny Seraphine
Moura, Bianca
Missiaglia, Edoardo
Aedo-Lopez, Veronica
Michielin, Olivier
Tsantoulis, Petros
Bisig, Bettina
Trimech, Mounir
Zoete, Vincent
Homicsko, Krisztian
author_facet Krebs, Fanny Seraphine
Moura, Bianca
Missiaglia, Edoardo
Aedo-Lopez, Veronica
Michielin, Olivier
Tsantoulis, Petros
Bisig, Bettina
Trimech, Mounir
Zoete, Vincent
Homicsko, Krisztian
author_sort Krebs, Fanny Seraphine
collection PubMed
description The development of targeted therapies for non-BRAF p.Val600-mutant melanomas remains a challenge. Triple wildtype (TWT) melanomas that lack mutations in BRAF, NRAS, or NF1 form 10% of human melanomas and are heterogeneous in their genomic drivers. MAP2K1 mutations are enriched in BRAF-mutant melanoma and function as an innate or adaptive resistance mechanism to BRAF inhibition. Here we report the case of a patient with TWT melanoma with a bona fide MAP2K1 mutation without any BRAF mutations. We performed a structural analysis to validate that the MEK inhibitor trametinib could block this mutation. Although the patient initially responded to trametinib, he eventually progressed. The presence of a CDKN2A deletion prompted us to combine a CDK4/6 inhibitor, palbociclib, with trametinib but without clinical benefit. Genomic analysis at progression showed multiple novel copy number alterations. Our case illustrates the challenges of combining MEK1 and CDK4/6 inhibitors in case of resistance to MEK inhibitor monotherapy.
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spelling pubmed-100031772023-03-11 Response and Resistance to Trametinib in MAP2K1-Mutant Triple-Negative Melanoma Krebs, Fanny Seraphine Moura, Bianca Missiaglia, Edoardo Aedo-Lopez, Veronica Michielin, Olivier Tsantoulis, Petros Bisig, Bettina Trimech, Mounir Zoete, Vincent Homicsko, Krisztian Int J Mol Sci Case Report The development of targeted therapies for non-BRAF p.Val600-mutant melanomas remains a challenge. Triple wildtype (TWT) melanomas that lack mutations in BRAF, NRAS, or NF1 form 10% of human melanomas and are heterogeneous in their genomic drivers. MAP2K1 mutations are enriched in BRAF-mutant melanoma and function as an innate or adaptive resistance mechanism to BRAF inhibition. Here we report the case of a patient with TWT melanoma with a bona fide MAP2K1 mutation without any BRAF mutations. We performed a structural analysis to validate that the MEK inhibitor trametinib could block this mutation. Although the patient initially responded to trametinib, he eventually progressed. The presence of a CDKN2A deletion prompted us to combine a CDK4/6 inhibitor, palbociclib, with trametinib but without clinical benefit. Genomic analysis at progression showed multiple novel copy number alterations. Our case illustrates the challenges of combining MEK1 and CDK4/6 inhibitors in case of resistance to MEK inhibitor monotherapy. MDPI 2023-02-24 /pmc/articles/PMC10003177/ /pubmed/36901951 http://dx.doi.org/10.3390/ijms24054520 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Case Report
Krebs, Fanny Seraphine
Moura, Bianca
Missiaglia, Edoardo
Aedo-Lopez, Veronica
Michielin, Olivier
Tsantoulis, Petros
Bisig, Bettina
Trimech, Mounir
Zoete, Vincent
Homicsko, Krisztian
Response and Resistance to Trametinib in MAP2K1-Mutant Triple-Negative Melanoma
title Response and Resistance to Trametinib in MAP2K1-Mutant Triple-Negative Melanoma
title_full Response and Resistance to Trametinib in MAP2K1-Mutant Triple-Negative Melanoma
title_fullStr Response and Resistance to Trametinib in MAP2K1-Mutant Triple-Negative Melanoma
title_full_unstemmed Response and Resistance to Trametinib in MAP2K1-Mutant Triple-Negative Melanoma
title_short Response and Resistance to Trametinib in MAP2K1-Mutant Triple-Negative Melanoma
title_sort response and resistance to trametinib in map2k1-mutant triple-negative melanoma
topic Case Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10003177/
https://www.ncbi.nlm.nih.gov/pubmed/36901951
http://dx.doi.org/10.3390/ijms24054520
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