Concurrent MEK2 Mutation and BRAF Amplification Confer Resistance to BRAF and MEK Inhibitors in Melanoma
Although BRAF and MEK inhibitors have proven clinical benefits in melanoma, most patients develop resistance. We report a de novo MEK2-Q60P mutation and BRAF gain in a melanoma from a patient who progressed on the MEK inhibitor trametinib and did not respond to the BRAF inhibitor dabrafenib. We also...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2013-09-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124713004646 |
| _version_ | 1818542758208471040 |
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| author | Jessie Villanueva Jeffrey R. Infante Clemens Krepler Patricia Reyes-Uribe Minu Samanta Hsin-Yi Chen Bin Li Rolf K. Swoboda Melissa Wilson Adina Vultur Mizuho Fukunaba-Kalabis Bradley Wubbenhorst Thomas Y. Chen Qin Liu Katrin Sproesser Douglas J. DeMarini Tona M. Gilmer Anne-Marie Martin Ronen Marmorstein David C. Schultz David W. Speicher Giorgos C. Karakousis Wei Xu Ravi K. Amaravadi Xiaowei Xu Lynn M. Schuchter Meenhard Herlyn Katherine L. Nathanson |
| author_facet | Jessie Villanueva Jeffrey R. Infante Clemens Krepler Patricia Reyes-Uribe Minu Samanta Hsin-Yi Chen Bin Li Rolf K. Swoboda Melissa Wilson Adina Vultur Mizuho Fukunaba-Kalabis Bradley Wubbenhorst Thomas Y. Chen Qin Liu Katrin Sproesser Douglas J. DeMarini Tona M. Gilmer Anne-Marie Martin Ronen Marmorstein David C. Schultz David W. Speicher Giorgos C. Karakousis Wei Xu Ravi K. Amaravadi Xiaowei Xu Lynn M. Schuchter Meenhard Herlyn Katherine L. Nathanson |
| author_sort | Jessie Villanueva |
| collection | DOAJ |
| description | Although BRAF and MEK inhibitors have proven clinical benefits in melanoma, most patients develop resistance. We report a de novo MEK2-Q60P mutation and BRAF gain in a melanoma from a patient who progressed on the MEK inhibitor trametinib and did not respond to the BRAF inhibitor dabrafenib. We also identified the same MEK2-Q60P mutation along with BRAF amplification in a xenograft tumor derived from a second melanoma patient resistant to the combination of dabrafenib and trametinib. Melanoma cells chronically exposed to trametinib acquired concurrent MEK2-Q60P mutation and BRAF-V600E amplification, which conferred resistance to MEK and BRAF inhibitors. The resistant cells had sustained MAPK activation and persistent phosphorylation of S6K. A triple combination of dabrafenib, trametinib, and the PI3K/mTOR inhibitor GSK2126458 led to sustained tumor growth inhibition. Hence, concurrent genetic events that sustain MAPK signaling can underlie resistance to both BRAF and MEK inhibitors, requiring novel therapeutic strategies to overcome it. |
| first_indexed | 2024-12-11T22:26:20Z |
| format | Article |
| id | doaj.art-def1fcb2813549cea0a237cf8e63bb48 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-11T22:26:20Z |
| publishDate | 2013-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-def1fcb2813549cea0a237cf8e63bb482022-12-22T00:48:16ZengElsevierCell Reports2211-12472013-09-01461090109910.1016/j.celrep.2013.08.023Concurrent MEK2 Mutation and BRAF Amplification Confer Resistance to BRAF and MEK Inhibitors in MelanomaJessie Villanueva0Jeffrey R. Infante1Clemens Krepler2Patricia Reyes-Uribe3Minu Samanta4Hsin-Yi Chen5Bin Li6Rolf K. Swoboda7Melissa Wilson8Adina Vultur9Mizuho Fukunaba-Kalabis10Bradley Wubbenhorst11Thomas Y. Chen12Qin Liu13Katrin Sproesser14Douglas J. DeMarini15Tona M. Gilmer16Anne-Marie Martin17Ronen Marmorstein18David C. Schultz19David W. Speicher20Giorgos C. Karakousis21Wei Xu22Ravi K. Amaravadi23Xiaowei Xu24Lynn M. Schuchter25Meenhard Herlyn26Katherine L. Nathanson27Molecular and Cellular Oncogenesis Program, Melanoma Research Center, The Wistar Institute, Philadelphia, PA 19104, USASarah Cannon Research Institute/Tennessee Oncology, PLLC, Nashville, TN 37203, USAMolecular and Cellular Oncogenesis Program, Melanoma Research Center, The Wistar Institute, Philadelphia, PA 19104, USAMolecular and Cellular Oncogenesis Program, Melanoma Research Center, The Wistar Institute, Philadelphia, PA 19104, USAMolecular and Cellular Oncogenesis Program, Melanoma Research Center, The Wistar Institute, Philadelphia, PA 19104, USAMolecular and Cellular Oncogenesis Program, Melanoma Research Center, The Wistar Institute, Philadelphia, PA 19104, USADivision of Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USAMolecular and Cellular Oncogenesis Program, Melanoma Research Center, The Wistar Institute, Philadelphia, PA 19104, USADivision of Hematology and Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USAMolecular and Cellular Oncogenesis Program, Melanoma Research Center, The Wistar Institute, Philadelphia, PA 19104, USAMolecular and Cellular Oncogenesis Program, Melanoma Research Center, The Wistar Institute, Philadelphia, PA 19104, USADivision of Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USAMolecular and Cellular Oncogenesis Program, Melanoma Research Center, The Wistar Institute, Philadelphia, PA 19104, USAMolecular and Cellular Oncogenesis Program, Melanoma Research Center, The Wistar Institute, Philadelphia, PA 19104, USAMolecular and Cellular Oncogenesis Program, Melanoma Research Center, The Wistar Institute, Philadelphia, PA 19104, USAOncology Research and Development, GlaxoSmithKline, Collegeville, PA 19426, USAOncology Research and Development, GlaxoSmithKline, Research Triangle Park, NC 27709, USAOncology Research and Development, GlaxoSmithKline, Collegeville, PA 19426, USAGene Expression and Regulation Program, Melanoma Research Center, The Wistar Institute, Philadelphia, PA 19104, USAGene Expression and Regulation Program, Melanoma Research Center, The Wistar Institute, Philadelphia, PA 19104, USAMolecular and Cellular Oncogenesis Program, Melanoma Research Center, The Wistar Institute, Philadelphia, PA 19104, USADivision of Hematology and Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USADivision of Hematology and Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USADivision of Hematology and Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USAAbramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USADivision of Hematology and Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USAMolecular and Cellular Oncogenesis Program, Melanoma Research Center, The Wistar Institute, Philadelphia, PA 19104, USADivision of Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USAAlthough BRAF and MEK inhibitors have proven clinical benefits in melanoma, most patients develop resistance. We report a de novo MEK2-Q60P mutation and BRAF gain in a melanoma from a patient who progressed on the MEK inhibitor trametinib and did not respond to the BRAF inhibitor dabrafenib. We also identified the same MEK2-Q60P mutation along with BRAF amplification in a xenograft tumor derived from a second melanoma patient resistant to the combination of dabrafenib and trametinib. Melanoma cells chronically exposed to trametinib acquired concurrent MEK2-Q60P mutation and BRAF-V600E amplification, which conferred resistance to MEK and BRAF inhibitors. The resistant cells had sustained MAPK activation and persistent phosphorylation of S6K. A triple combination of dabrafenib, trametinib, and the PI3K/mTOR inhibitor GSK2126458 led to sustained tumor growth inhibition. Hence, concurrent genetic events that sustain MAPK signaling can underlie resistance to both BRAF and MEK inhibitors, requiring novel therapeutic strategies to overcome it.http://www.sciencedirect.com/science/article/pii/S2211124713004646 |
| spellingShingle | Jessie Villanueva Jeffrey R. Infante Clemens Krepler Patricia Reyes-Uribe Minu Samanta Hsin-Yi Chen Bin Li Rolf K. Swoboda Melissa Wilson Adina Vultur Mizuho Fukunaba-Kalabis Bradley Wubbenhorst Thomas Y. Chen Qin Liu Katrin Sproesser Douglas J. DeMarini Tona M. Gilmer Anne-Marie Martin Ronen Marmorstein David C. Schultz David W. Speicher Giorgos C. Karakousis Wei Xu Ravi K. Amaravadi Xiaowei Xu Lynn M. Schuchter Meenhard Herlyn Katherine L. Nathanson Concurrent MEK2 Mutation and BRAF Amplification Confer Resistance to BRAF and MEK Inhibitors in Melanoma Cell Reports |
| title | Concurrent MEK2 Mutation and BRAF Amplification Confer Resistance to BRAF and MEK Inhibitors in Melanoma |
| title_full | Concurrent MEK2 Mutation and BRAF Amplification Confer Resistance to BRAF and MEK Inhibitors in Melanoma |
| title_fullStr | Concurrent MEK2 Mutation and BRAF Amplification Confer Resistance to BRAF and MEK Inhibitors in Melanoma |
| title_full_unstemmed | Concurrent MEK2 Mutation and BRAF Amplification Confer Resistance to BRAF and MEK Inhibitors in Melanoma |
| title_short | Concurrent MEK2 Mutation and BRAF Amplification Confer Resistance to BRAF and MEK Inhibitors in Melanoma |
| title_sort | concurrent mek2 mutation and braf amplification confer resistance to braf and mek inhibitors in melanoma |
| url | http://www.sciencedirect.com/science/article/pii/S2211124713004646 |
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