Response and Resistance to Trametinib in MAP2K1-Mutant Triple-Negative Melanoma
The development of targeted therapies for non-<i>BRAF</i> p.Val600-mutant melanomas remains a challenge. Triple wildtype (TWT) melanomas that lack mutations in <i>BRAF</i>, <i>NRAS</i>, or <i>NF1</i> form 10% of human melanomas and are heterogeneous in...
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MDPI AG
2023-02-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/5/4520 |
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| author | Fanny Seraphine Krebs Bianca Moura Edoardo Missiaglia Veronica Aedo-Lopez Olivier Michielin Petros Tsantoulis Bettina Bisig Mounir Trimech Vincent Zoete Krisztian Homicsko |
| author_facet | Fanny Seraphine Krebs Bianca Moura Edoardo Missiaglia Veronica Aedo-Lopez Olivier Michielin Petros Tsantoulis Bettina Bisig Mounir Trimech Vincent Zoete Krisztian Homicsko |
| author_sort | Fanny Seraphine Krebs |
| collection | DOAJ |
| description | The development of targeted therapies for non-<i>BRAF</i> p.Val600-mutant melanomas remains a challenge. Triple wildtype (TWT) melanomas that lack mutations in <i>BRAF</i>, <i>NRAS</i>, or <i>NF1</i> form 10% of human melanomas and are heterogeneous in their genomic drivers. <i>MAP2K1</i> mutations are enriched in <i>BRAF</i>-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 <i>MAP2K1</i> mutation without any <i>BRAF</i> 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 <i>CDKN2A</i> 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. |
| first_indexed | 2024-03-11T07:22:38Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T07:22:38Z |
| publishDate | 2023-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-6e05220d67084f598aef1d934deb70082023-11-17T07:49:37ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-02-01245452010.3390/ijms24054520Response and Resistance to Trametinib in MAP2K1-Mutant Triple-Negative MelanomaFanny Seraphine Krebs0Bianca Moura1Edoardo Missiaglia2Veronica Aedo-Lopez3Olivier Michielin4Petros Tsantoulis5Bettina Bisig6Mounir Trimech7Vincent Zoete8Krisztian Homicsko9Computer-Aided Molecular Engineering, Department of Oncology UNIL-CHUV, University of Lausanne, 1015 Lausanne, SwitzerlandService of Medical Oncology, 1700 Fribourg, SwitzerlandDepartment of Laboratory Medicine and Pathology, Institute of Pathology, Centre Hospitalier Universitaire Vaudois, Lausanne University, 1011 Lausanne, SwitzerlandMonash Medical Centre, Clayton, VIC 3168, AustraliaMolecular Modelling Group, SIB Swiss Institute of Bioinformatics, 1015 Lausanne, SwitzerlandSwiss Cancer Center Leman, 1005 Lausanne, SwitzerlandDepartment of Laboratory Medicine and Pathology, Institute of Pathology, Centre Hospitalier Universitaire Vaudois, Lausanne University, 1011 Lausanne, SwitzerlandDepartment of Laboratory Medicine and Pathology, Institute of Pathology, Centre Hospitalier Universitaire Vaudois, Lausanne University, 1011 Lausanne, SwitzerlandComputer-Aided Molecular Engineering, Department of Oncology UNIL-CHUV, University of Lausanne, 1015 Lausanne, SwitzerlandLudwig Institute for Cancer Research, 1005 Lausanne, SwitzerlandThe development of targeted therapies for non-<i>BRAF</i> p.Val600-mutant melanomas remains a challenge. Triple wildtype (TWT) melanomas that lack mutations in <i>BRAF</i>, <i>NRAS</i>, or <i>NF1</i> form 10% of human melanomas and are heterogeneous in their genomic drivers. <i>MAP2K1</i> mutations are enriched in <i>BRAF</i>-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 <i>MAP2K1</i> mutation without any <i>BRAF</i> 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 <i>CDKN2A</i> 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.https://www.mdpi.com/1422-0067/24/5/4520cancer<i>MAP2K1</i>triple-negative melanomamodellingmutation |
| spellingShingle | Fanny Seraphine Krebs Bianca Moura Edoardo Missiaglia Veronica Aedo-Lopez Olivier Michielin Petros Tsantoulis Bettina Bisig Mounir Trimech Vincent Zoete Krisztian Homicsko Response and Resistance to Trametinib in MAP2K1-Mutant Triple-Negative Melanoma International Journal of Molecular Sciences cancer <i>MAP2K1</i> triple-negative melanoma modelling mutation |
| 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 | cancer <i>MAP2K1</i> triple-negative melanoma modelling mutation |
| url | https://www.mdpi.com/1422-0067/24/5/4520 |
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