Co‐targeting BET and MEK as salvage therapy for MAPK and checkpoint inhibitor‐resistant melanoma
| Autor: | Yiling Lu, Genevieve M. Boland, Jessie Villanueva, Clemens Krepler, Adam N. Guterres, Rajasekharan Somasundaram, Christin E. Burd, Qin Liu, Dennie T. Frederick, Chaoran Cheng, Andrew V. Kossenkov, Gao Zhang, Ashani T. Weeraratna, Patricia Reyes-Uribe, Gordon B. Mills, Xiaowei Xu, Ravi K. Amaravadi, Ryan J. Sullivan, Andrew E. Aplin, Xiangfan Yin, Keith T. Flaherty, Miao Benchun, Lynn M. Schuchter, Giorgos C. Karakousis, Zhi Wei, Ileabett M. Echevarria-Vargas, Wei Xu, Meenhard Herlyn, Jennifer J.D. Morrissette |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
MAPK/ERK pathway Medicine (General) BRD4 Combination therapy medicine.medical_treatment Salvage therapy Drug resistance QH426-470 combination therapy 03 medical and health sciences R5-920 melanoma Genetics Medicine drug resistance business.industry Melanoma Cancer hemic and immune systems Immunotherapy BET medicine.disease 3. Good health mutant NRAS 030104 developmental biology Cancer research Molecular Medicine business |
| Zdroj: | EMBO Molecular Medicine, Vol 10, Iss 5, Pp n/a-n/a (2018) |
| ISSN: | 1757-4684 1757-4676 |
| DOI: | 10.15252/emmm.201708446 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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