Co‐targeting BET and MEK as salvage therapy for MAPK and checkpoint inhibitor‐resistant melanoma
Abstract Despite novel therapies for melanoma, drug resistance remains a significant hurdle to achieving optimal responses. NRAS‐mutant melanoma is an archetype of therapeutic challenges in the field, which we used to test drug combinations to avert drug resistance. We show that BET proteins are ove...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Springer Nature
2018-04-01
|
| Series: | EMBO Molecular Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.15252/emmm.201708446 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849761755843002368 |
|---|---|
| author | Ileabett M Echevarría‐Vargas Patricia I Reyes‐Uribe Adam N Guterres Xiangfan Yin Andrew V Kossenkov Qin Liu Gao Zhang Clemens Krepler Chaoran Cheng Zhi Wei Rajasekharan Somasundaram Giorgos Karakousis Wei Xu Jennifer JD Morrissette Yiling Lu Gordon B Mills Ryan J Sullivan Miao Benchun Dennie T Frederick Genevieve Boland Keith T Flaherty Ashani T Weeraratna Meenhard Herlyn Ravi Amaravadi Lynn M Schuchter Christin E Burd Andrew E Aplin Xiaowei Xu Jessie Villanueva |
| author_facet | Ileabett M Echevarría‐Vargas Patricia I Reyes‐Uribe Adam N Guterres Xiangfan Yin Andrew V Kossenkov Qin Liu Gao Zhang Clemens Krepler Chaoran Cheng Zhi Wei Rajasekharan Somasundaram Giorgos Karakousis Wei Xu Jennifer JD Morrissette Yiling Lu Gordon B Mills Ryan J Sullivan Miao Benchun Dennie T Frederick Genevieve Boland Keith T Flaherty Ashani T Weeraratna Meenhard Herlyn Ravi Amaravadi Lynn M Schuchter Christin E Burd Andrew E Aplin Xiaowei Xu Jessie Villanueva |
| author_sort | Ileabett M Echevarría‐Vargas |
| collection | DOAJ |
| description | Abstract Despite novel therapies for melanoma, drug resistance remains a significant hurdle to achieving optimal responses. NRAS‐mutant melanoma is an archetype of therapeutic challenges in the field, which we used to test drug combinations to avert drug resistance. We show that BET proteins are overexpressed in NRAS‐mutant melanoma and that high levels of the BET family member BRD4 are associated with poor patient survival. Combining BET and MEK inhibitors synergistically curbed the growth of NRAS‐mutant melanoma and prolonged the survival of mice bearing tumors refractory to MAPK inhibitors and immunotherapy. Transcriptomic and proteomic analysis revealed that combining BET and MEK inhibitors mitigates a MAPK and checkpoint inhibitor resistance transcriptional signature, downregulates the transcription factor TCF19, and induces apoptosis. Our studies demonstrate that co‐targeting MEK and BET can offset therapy resistance, offering a salvage strategy for melanomas with no other therapeutic options, and possibly other treatment‐resistant tumor types. |
| format | Article |
| id | doaj-art-427671eabd2f438dbb2812ca02f929e3 |
| institution | DOAJ |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2018-04-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-427671eabd2f438dbb2812ca02f929e32025-08-20T03:05:55ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842018-04-0110511510.15252/emmm.201708446Co‐targeting BET and MEK as salvage therapy for MAPK and checkpoint inhibitor‐resistant melanomaIleabett M Echevarría‐Vargas0Patricia I Reyes‐Uribe1Adam N Guterres2Xiangfan Yin3Andrew V Kossenkov4Qin Liu5Gao Zhang6Clemens Krepler7Chaoran Cheng8Zhi Wei9Rajasekharan Somasundaram10Giorgos Karakousis11Wei Xu12Jennifer JD Morrissette13Yiling Lu14Gordon B Mills15Ryan J Sullivan16Miao Benchun17Dennie T Frederick18Genevieve Boland19Keith T Flaherty20Ashani T Weeraratna21Meenhard Herlyn22Ravi Amaravadi23Lynn M Schuchter24Christin E Burd25Andrew E Aplin26Xiaowei Xu27Jessie Villanueva28Molecular & Cellular Oncogenesis Program, The Wistar InstituteMolecular & Cellular Oncogenesis Program, The Wistar InstituteMolecular & Cellular Oncogenesis Program, The Wistar InstituteMolecular & Cellular Oncogenesis Program, The Wistar InstituteMolecular & Cellular Oncogenesis Program, The Wistar InstituteMolecular & Cellular Oncogenesis Program, The Wistar InstituteMolecular & Cellular Oncogenesis Program, The Wistar InstituteMolecular & Cellular Oncogenesis Program, The Wistar InstituteCollege of Computing Sciences, New Jersey Institute of TechnologyCollege of Computing Sciences, New Jersey Institute of TechnologyMolecular & Cellular Oncogenesis Program, The Wistar InstituteAbramson Cancer Center, University of PennsylvaniaAbramson Cancer Center, University of PennsylvaniaCenter for Personalized Diagnostics, Hospital of the University of Pennsylvania, University of PennsylvaniaDepartment of Systems Biology, The University of Texas MD Anderson Cancer CenterDepartment of Systems Biology, The University of Texas MD Anderson Cancer CenterMassachusetts General Hospital Cancer Center, Harvard Medical SchoolMassachusetts General Hospital Cancer Center, Harvard Medical SchoolMassachusetts General Hospital Cancer Center, Harvard Medical SchoolDepartment of Surgery, Massachusetts General Hospital, Harvard Medical SchoolMassachusetts General Hospital Cancer Center, Harvard Medical SchoolMelanoma Research Center, The Wistar InstituteMolecular & Cellular Oncogenesis Program, The Wistar InstituteDepartment of Surgery, Hospital of the University of PennsylvaniaDepartment of Surgery, Hospital of the University of PennsylvaniaDepartments of Molecular Genetics and Cancer Biology and Genetics, Ohio State UniversityDepartment of Cancer Biology and Sidney Kimmel Cancer Center, Thomas Jefferson UniversityDepartment of Surgery, Hospital of the University of PennsylvaniaMolecular & Cellular Oncogenesis Program, The Wistar InstituteAbstract Despite novel therapies for melanoma, drug resistance remains a significant hurdle to achieving optimal responses. NRAS‐mutant melanoma is an archetype of therapeutic challenges in the field, which we used to test drug combinations to avert drug resistance. We show that BET proteins are overexpressed in NRAS‐mutant melanoma and that high levels of the BET family member BRD4 are associated with poor patient survival. Combining BET and MEK inhibitors synergistically curbed the growth of NRAS‐mutant melanoma and prolonged the survival of mice bearing tumors refractory to MAPK inhibitors and immunotherapy. Transcriptomic and proteomic analysis revealed that combining BET and MEK inhibitors mitigates a MAPK and checkpoint inhibitor resistance transcriptional signature, downregulates the transcription factor TCF19, and induces apoptosis. Our studies demonstrate that co‐targeting MEK and BET can offset therapy resistance, offering a salvage strategy for melanomas with no other therapeutic options, and possibly other treatment‐resistant tumor types.https://doi.org/10.15252/emmm.201708446BETcombination therapydrug resistancemelanomamutant NRAS |
| spellingShingle | Ileabett M Echevarría‐Vargas Patricia I Reyes‐Uribe Adam N Guterres Xiangfan Yin Andrew V Kossenkov Qin Liu Gao Zhang Clemens Krepler Chaoran Cheng Zhi Wei Rajasekharan Somasundaram Giorgos Karakousis Wei Xu Jennifer JD Morrissette Yiling Lu Gordon B Mills Ryan J Sullivan Miao Benchun Dennie T Frederick Genevieve Boland Keith T Flaherty Ashani T Weeraratna Meenhard Herlyn Ravi Amaravadi Lynn M Schuchter Christin E Burd Andrew E Aplin Xiaowei Xu Jessie Villanueva Co‐targeting BET and MEK as salvage therapy for MAPK and checkpoint inhibitor‐resistant melanoma EMBO Molecular Medicine BET combination therapy drug resistance melanoma mutant NRAS |
| title | Co‐targeting BET and MEK as salvage therapy for MAPK and checkpoint inhibitor‐resistant melanoma |
| title_full | Co‐targeting BET and MEK as salvage therapy for MAPK and checkpoint inhibitor‐resistant melanoma |
| title_fullStr | Co‐targeting BET and MEK as salvage therapy for MAPK and checkpoint inhibitor‐resistant melanoma |
| title_full_unstemmed | Co‐targeting BET and MEK as salvage therapy for MAPK and checkpoint inhibitor‐resistant melanoma |
| title_short | Co‐targeting BET and MEK as salvage therapy for MAPK and checkpoint inhibitor‐resistant melanoma |
| title_sort | co targeting bet and mek as salvage therapy for mapk and checkpoint inhibitor resistant melanoma |
| topic | BET combination therapy drug resistance melanoma mutant NRAS |
| url | https://doi.org/10.15252/emmm.201708446 |
| work_keys_str_mv | AT ileabettmechevarriavargas cotargetingbetandmekassalvagetherapyformapkandcheckpointinhibitorresistantmelanoma AT patriciaireyesuribe cotargetingbetandmekassalvagetherapyformapkandcheckpointinhibitorresistantmelanoma AT adamnguterres cotargetingbetandmekassalvagetherapyformapkandcheckpointinhibitorresistantmelanoma AT xiangfanyin cotargetingbetandmekassalvagetherapyformapkandcheckpointinhibitorresistantmelanoma AT andrewvkossenkov cotargetingbetandmekassalvagetherapyformapkandcheckpointinhibitorresistantmelanoma AT qinliu cotargetingbetandmekassalvagetherapyformapkandcheckpointinhibitorresistantmelanoma AT gaozhang cotargetingbetandmekassalvagetherapyformapkandcheckpointinhibitorresistantmelanoma AT clemenskrepler cotargetingbetandmekassalvagetherapyformapkandcheckpointinhibitorresistantmelanoma AT chaorancheng cotargetingbetandmekassalvagetherapyformapkandcheckpointinhibitorresistantmelanoma AT zhiwei cotargetingbetandmekassalvagetherapyformapkandcheckpointinhibitorresistantmelanoma AT rajasekharansomasundaram cotargetingbetandmekassalvagetherapyformapkandcheckpointinhibitorresistantmelanoma AT giorgoskarakousis cotargetingbetandmekassalvagetherapyformapkandcheckpointinhibitorresistantmelanoma AT weixu cotargetingbetandmekassalvagetherapyformapkandcheckpointinhibitorresistantmelanoma AT jenniferjdmorrissette cotargetingbetandmekassalvagetherapyformapkandcheckpointinhibitorresistantmelanoma AT yilinglu cotargetingbetandmekassalvagetherapyformapkandcheckpointinhibitorresistantmelanoma AT gordonbmills cotargetingbetandmekassalvagetherapyformapkandcheckpointinhibitorresistantmelanoma AT ryanjsullivan cotargetingbetandmekassalvagetherapyformapkandcheckpointinhibitorresistantmelanoma AT miaobenchun cotargetingbetandmekassalvagetherapyformapkandcheckpointinhibitorresistantmelanoma AT dennietfrederick cotargetingbetandmekassalvagetherapyformapkandcheckpointinhibitorresistantmelanoma AT genevieveboland cotargetingbetandmekassalvagetherapyformapkandcheckpointinhibitorresistantmelanoma AT keithtflaherty cotargetingbetandmekassalvagetherapyformapkandcheckpointinhibitorresistantmelanoma AT ashanitweeraratna cotargetingbetandmekassalvagetherapyformapkandcheckpointinhibitorresistantmelanoma AT meenhardherlyn cotargetingbetandmekassalvagetherapyformapkandcheckpointinhibitorresistantmelanoma AT raviamaravadi cotargetingbetandmekassalvagetherapyformapkandcheckpointinhibitorresistantmelanoma AT lynnmschuchter cotargetingbetandmekassalvagetherapyformapkandcheckpointinhibitorresistantmelanoma AT christineburd cotargetingbetandmekassalvagetherapyformapkandcheckpointinhibitorresistantmelanoma AT andreweaplin cotargetingbetandmekassalvagetherapyformapkandcheckpointinhibitorresistantmelanoma AT xiaoweixu cotargetingbetandmekassalvagetherapyformapkandcheckpointinhibitorresistantmelanoma AT jessievillanueva cotargetingbetandmekassalvagetherapyformapkandcheckpointinhibitorresistantmelanoma |