Co-targeting BET and MEK as salvage therapy for MAPK and checkpoint inhibitor-resistant melanoma

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 J.D. 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

doi:10.15252/emmm.201708446

Co-targeting BET and MEK as salvage therapy for MAPK and checkpoint inhibitor-resistant melanoma

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 J.D. Morrissette, Yiling Lu, Gordon B. Mills, Ryan J. Sullivan, Miao Benchun, Dennie T. Frederick, Genevieve BolandKeith T. Flaherty, Ashani T. Weeraratna, Meenhard Herlyn, Ravi Amaravadi, Lynn M. Schuchter, Christin E. Burd, Andrew E. Aplin, Xiaowei Xu, Jessie Villanueva

Research output: Contribution to journal › Article › peer-review

68 Scopus citations

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.

Original language	English (US)
Article number	e8446
Journal	EMBO Molecular Medicine
Volume	10
Issue number	5
DOIs	https://doi.org/10.15252/emmm.201708446
State	Published - May 2018
Externally published	Yes

All Science Journal Classification (ASJC) codes

Molecular Medicine

Keywords

BET
combination therapy
drug resistance
melanoma
mutant NRAS

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Echevarría-Vargas, I. M., Reyes-Uribe, P. I., Guterres, A. N., Yin, X., Kossenkov, A. V., Liu, Q., Zhang, G., Krepler, C., Cheng, C., Wei, Z., Somasundaram, R., Karakousis, G., Xu, W., Morrissette, J. J. D., Lu, Y., Mills, G. B., Sullivan, R. J., Benchun, M., Frederick, D. T., ... Villanueva, J. (2018). Co-targeting BET and MEK as salvage therapy for MAPK and checkpoint inhibitor-resistant melanoma. EMBO Molecular Medicine, 10(5), Article e8446. https://doi.org/10.15252/emmm.201708446

@article{ce45045d446b4bd28f5a184b23234ffc,

title = "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 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.",

keywords = "BET, combination therapy, drug resistance, melanoma, mutant NRAS",

author = "Echevarr{\'i}a-Vargas, {Ileabett M.} and Reyes-Uribe, {Patricia I.} and Guterres, {Adam N.} and Xiangfan Yin and Kossenkov, {Andrew V.} and Qin Liu and Gao Zhang and Clemens Krepler and Chaoran Cheng and Zhi Wei and Rajasekharan Somasundaram and Giorgos Karakousis and Wei Xu and Morrissette, {Jennifer J.D.} and Yiling Lu and Mills, {Gordon B.} and Sullivan, {Ryan J.} and Miao Benchun and Frederick, {Dennie T.} and Genevieve Boland and Flaherty, {Keith T.} and Weeraratna, {Ashani T.} and Meenhard Herlyn and Ravi Amaravadi and Schuchter, {Lynn M.} and Burd, {Christin E.} and Aplin, {Andrew E.} and Xiaowei Xu and Jessie Villanueva",

note = "Publisher Copyright: {\textcopyright} 2018 The Authors. Published under the terms of the CC BY 4.0 license",

year = "2018",

month = may,

doi = "10.15252/emmm.201708446",

language = "English (US)",

volume = "10",

journal = "EMBO Molecular Medicine",

issn = "1757-4676",

publisher = "Springer International Publishing",

number = "5",

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Echevarría-Vargas, IM, Reyes-Uribe, PI, Guterres, AN, Yin, X, Kossenkov, AV, Liu, Q, Zhang, G, Krepler, C, Cheng, C, Wei, Z, Somasundaram, R, Karakousis, G, Xu, W, Morrissette, JJD, Lu, Y, Mills, GB, Sullivan, RJ, Benchun, M, Frederick, DT, Boland, G, Flaherty, KT, Weeraratna, AT, Herlyn, M, Amaravadi, R, Schuchter, LM, Burd, CE, Aplin, AE, Xu, X & Villanueva, J 2018, 'Co-targeting BET and MEK as salvage therapy for MAPK and checkpoint inhibitor-resistant melanoma', EMBO Molecular Medicine, vol. 10, no. 5, e8446. https://doi.org/10.15252/emmm.201708446

TY - JOUR

T1 - Co-targeting BET and MEK as salvage therapy for MAPK and checkpoint inhibitor-resistant melanoma

AU - Echevarría-Vargas, Ileabett M.

AU - Reyes-Uribe, Patricia I.

AU - Guterres, Adam N.

AU - Yin, Xiangfan

AU - Kossenkov, Andrew V.

AU - Liu, Qin

AU - Zhang, Gao

AU - Krepler, Clemens

AU - Cheng, Chaoran

AU - Wei, Zhi

AU - Somasundaram, Rajasekharan

AU - Karakousis, Giorgos

AU - Xu, Wei

AU - Morrissette, Jennifer J.D.

AU - Lu, Yiling

AU - Mills, Gordon B.

AU - Sullivan, Ryan J.

AU - Benchun, Miao

AU - Frederick, Dennie T.

AU - Boland, Genevieve

AU - Flaherty, Keith T.

AU - Weeraratna, Ashani T.

AU - Herlyn, Meenhard

AU - Amaravadi, Ravi

AU - Schuchter, Lynn M.

AU - Burd, Christin E.

AU - Aplin, Andrew E.

AU - Xu, Xiaowei

AU - Villanueva, Jessie

PY - 2018/5

Y1 - 2018/5

N2 - 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.

AB - 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.

KW - BET

KW - combination therapy

KW - drug resistance

KW - melanoma

KW - mutant NRAS

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U2 - 10.15252/emmm.201708446

DO - 10.15252/emmm.201708446

M3 - Article

C2 - 29650805

AN - SCOPUS:85045707247

SN - 1757-4676

VL - 10

JO - EMBO Molecular Medicine

JF - EMBO Molecular Medicine

IS - 5

M1 - e8446

ER -

Co-targeting BET and MEK as salvage therapy for MAPK and checkpoint inhibitor-resistant melanoma

Abstract

All Science Journal Classification (ASJC) codes

Keywords

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