Co‐targeting BET and MEK as salvage therapy for MAPK and checkpoint inhibitor‐resistant melanoma. Issue 5 (11th April 2018)

• Record Type: Journal Article
• Authors: Echevarría‐Vargas, Ileabett M; Reyes‐Uribe, Patricia I; Guterres, Adam N; Yin, Xiangfan; Kossenkov, Andrew V; Liu, Qin; Zhang, Gao; Krepler, Clemens; Cheng, Chaoran; Wei, Zhi; Somasundaram, Rajasekharan; Karakousis, Giorgos; Xu, Wei; Morrissette, Jennifer JD; Lu, Yiling; Mills, Gordon B; Sullivan, Ryan J; Benchun, Miao; Frederick, Dennie T; Boland, Genevieve; Flaherty, Keith T; Weeraratna, Ashani T; Herlyn, Meenhard; Amaravadi, Ravi; Schuchter, Lynn M; Burd, Christin E; Aplin, Andrew E; Xu, Xiaowei; Villanueva, Jessie
• Is Part Of: EMBO molecular medicine. Volume 10:Issue 5(2018)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2018-04-11
• Subjects: BET -- combination therapy -- drug resistance -- melanoma -- mutant NRAS; Molecular biology -- Periodicals; Medical genetics -- Periodicals; Pathology, Molecular -- Periodicals; 616.04205
• DOI: 10.15252/emmm.201708446
• Languages: English
• ISSNs: 1757-4676

Abstract

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. Synopsis: Oncogenic NRAS has been deemed undrugabble; an alternative approach is to target NRAS effectors and non‐oncogene addictions. Co‐targeting MEK and BET synergistically downregulated TCF19 and restrained the growth of NRAS Mut melanoma tumors including tumors resistant to targeted and immunotherapies. High BRD4 levels are associated with poor outcome in NRAS Mut melanoma patients, suggesting that BRD4 plays a key role and hence, constitutes a vulnerability that can be therapeutically exploited. Combining BET and MEK inhibitors restrained the growth of NRAS Mut melanoma and prolonged the survival of mice bearing tumors refractory to MAPK and checkpoint inhibitors with no overt toxicity. Co‐targeting BET and MEK mitigates a MAPK‐ and checkpoint‐inhibitor resistance transcriptional signature (IPRES) and downregulates the transcription factor TCF19. TCF19 blockade triggers apoptosis of NRAS Mut melanoma cells. Downregulation of TCF19 is associated with response to targeted or immunotherapies. Abstract : Oncogenic NRAS has been deemed undrugabble; an alternative approach is to target NRAS effectors and non‐oncogene addictions. Co‐targeting MEK and BET synergistically downregulated TCF19 and restrained the growth of NRAS Mut melanoma tumors including tumors resistant to targeted and immunotherapies.