A screen for combination therapies in BRAF/NRAS wild type melanoma identifies nilotinib plus MEK inhibitor as a synergistic combination

Marco Ranzani; Kristel Kemper; Magali Michaut; Oscar Krijgsman; Nanne Aben; Vivek Iyer; Kim Wong; Theodoros I. Roumeliotis; Martin Del Castillo Velasco-Herrera; Jérémie Nsengimana; Gemma Turner; Nicola Thompson; Aida Shahrabi; Marcela Sjoberg; Mamunur Rashid; Anneliese O. Speak; Vera Grinkevich; Fiona Behan; David Tamborero; Francesco Iorio; Stijn van Dongen; Graham R. Bignell; Clara Alsinet; Sofia Chen; Emmanuelle Supper; Ken Dutton-Regester; Antonia Pritchard; Chi Wong; Anton Enright; Julia Newton-Bishop; Ultan McDermott; Nicholas K. Hayward; Jyoti S. Choudhary; Kosuke Yusa; Lodewyk Wessels; Mathew J. Garnett; Daniel Peeper; David J. Adams

doi:10.1101/195354

A screen for combination therapies in BRAF/NRAS wild type melanoma identifies nilotinib plus MEK inhibitor as a synergistic combination

Marco Ranzani, Kristel Kemper, Magali Michaut, Oscar Krijgsman, Nanne Aben, Vivek Iyer, Kim Wong, Theodoros I. Roumeliotis, Martin Del Castillo Velasco-Herrera, Jérémie Nsengimana, Gemma Turner, Nicola Thompson, Aida Shahrabi, Marcela Sjoberg, Mamunur Rashid, Anneliese O. Speak, Vera Grinkevich, Fiona Behan, David Tamborero, Francesco IorioStijn van Dongen, Graham R. Bignell, Clara Alsinet, Sofia Chen, Emmanuelle Supper, Ken Dutton-Regester, Antonia Pritchard, Chi Wong, Anton Enright, Julia Newton-Bishop, Ultan McDermott, Nicholas K. Hayward, Jyoti S. Choudhary, Kosuke Yusa, Lodewyk Wessels, Mathew J. Garnett, Daniel Peeper, David J. Adams

Research output: Working paper/Preprint › Preprint

Abstract

Despite recent therapeutic advances in the management of BRAF^V600-mutant melanoma, there is still a compelling need for more effective treatments for patients who developed BRAF/NRAS wild type disease. Since the activity of single targeted agents is limited by innate and acquired resistance, we performed a high-throughput drug screen using 180 drug combinations to generate over 18,000 viability curves, with the aim of identifying agents that synergise to kill BRAF/NRAS wild type melanoma cells. From this screen we observed strong synergy between the tyrosine kinase inhibitor nilotinib and MEK inhibitors and validated this combination in an independent cell line collection. We found that AXL expression was associated with synergy to the nilotinib/MEK inhibitor combination, and that both drugs work in concert to suppress pERK. This finding was supported by genome-wide CRISPR screening which revealed that resistance mechanisms converge on regulators of the MAPK pathway. Finally, we validated the synergy of nilotinib/trametinib combination in vivo using patient-derived xenografts. Our results indicate that a nilotinib/MEK inhibitor combination may represent an effective therapy in BRAF/NRAS wild type melanoma patients.

Original language	English
Publisher	bioRxiv
DOIs	https://doi.org/10.1101/195354
Publication status	Published - 28 Sept 2017

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Ranzani, M., Kemper, K., Michaut, M., Krijgsman, O., Aben, N., Iyer, V., Wong, K., Roumeliotis, T. I., Velasco-Herrera, M. D. C., Nsengimana, J., Turner, G., Thompson, N., Shahrabi, A., Sjoberg, M., Rashid, M., Speak, A. O., Grinkevich, V., Behan, F., Tamborero, D., ... Adams, D. J. (2017). A screen for combination therapies in BRAF/NRAS wild type melanoma identifies nilotinib plus MEK inhibitor as a synergistic combination. bioRxiv. https://doi.org/10.1101/195354

@techreport{47215fbf77c74a828c994072986c7289,

title = "A screen for combination therapies in BRAF/NRAS wild type melanoma identifies nilotinib plus MEK inhibitor as a synergistic combination",

abstract = "Despite recent therapeutic advances in the management of BRAFV600-mutant melanoma, there is still a compelling need for more effective treatments for patients who developed BRAF/NRAS wild type disease. Since the activity of single targeted agents is limited by innate and acquired resistance, we performed a high-throughput drug screen using 180 drug combinations to generate over 18,000 viability curves, with the aim of identifying agents that synergise to kill BRAF/NRAS wild type melanoma cells. From this screen we observed strong synergy between the tyrosine kinase inhibitor nilotinib and MEK inhibitors and validated this combination in an independent cell line collection. We found that AXL expression was associated with synergy to the nilotinib/MEK inhibitor combination, and that both drugs work in concert to suppress pERK. This finding was supported by genome-wide CRISPR screening which revealed that resistance mechanisms converge on regulators of the MAPK pathway. Finally, we validated the synergy of nilotinib/trametinib combination in vivo using patient-derived xenografts. Our results indicate that a nilotinib/MEK inhibitor combination may represent an effective therapy in BRAF/NRAS wild type melanoma patients.",

author = "Marco Ranzani and Kristel Kemper and Magali Michaut and Oscar Krijgsman and Nanne Aben and Vivek Iyer and Kim Wong and Roumeliotis, {Theodoros I.} and Velasco-Herrera, {Martin Del Castillo} and J{\'e}r{\'e}mie Nsengimana and Gemma Turner and Nicola Thompson and Aida Shahrabi and Marcela Sjoberg and Mamunur Rashid and Speak, {Anneliese O.} and Vera Grinkevich and Fiona Behan and David Tamborero and Francesco Iorio and {van Dongen}, Stijn and Bignell, {Graham R.} and Clara Alsinet and Sofia Chen and Emmanuelle Supper and Ken Dutton-Regester and Antonia Pritchard and Chi Wong and Anton Enright and Julia Newton-Bishop and Ultan McDermott and Hayward, {Nicholas K.} and Choudhary, {Jyoti S.} and Kosuke Yusa and Lodewyk Wessels and Garnett, {Mathew J.} and Daniel Peeper and Adams, {David J.}",

year = "2017",

month = sep,

day = "28",

doi = "10.1101/195354",

language = "English",

publisher = "bioRxiv",

type = "WorkingPaper",

institution = "bioRxiv",

}

Ranzani, M, Kemper, K, Michaut, M, Krijgsman, O, Aben, N, Iyer, V, Wong, K, Roumeliotis, TI, Velasco-Herrera, MDC, Nsengimana, J, Turner, G, Thompson, N, Shahrabi, A, Sjoberg, M, Rashid, M, Speak, AO, Grinkevich, V, Behan, F, Tamborero, D, Iorio, F, van Dongen, S, Bignell, GR, Alsinet, C, Chen, S, Supper, E, Dutton-Regester, K, Pritchard, A, Wong, C, Enright, A, Newton-Bishop, J, McDermott, U, Hayward, NK, Choudhary, JS, Yusa, K, Wessels, L, Garnett, MJ, Peeper, D & Adams, DJ 2017 'A screen for combination therapies in BRAF/NRAS wild type melanoma identifies nilotinib plus MEK inhibitor as a synergistic combination' bioRxiv. https://doi.org/10.1101/195354

TY - UNPB

T1 - A screen for combination therapies in BRAF/NRAS wild type melanoma identifies nilotinib plus MEK inhibitor as a synergistic combination

AU - Ranzani, Marco

AU - Kemper, Kristel

AU - Michaut, Magali

AU - Krijgsman, Oscar

AU - Aben, Nanne

AU - Iyer, Vivek

AU - Wong, Kim

AU - Roumeliotis, Theodoros I.

AU - Velasco-Herrera, Martin Del Castillo

AU - Nsengimana, Jérémie

AU - Turner, Gemma

AU - Thompson, Nicola

AU - Shahrabi, Aida

AU - Sjoberg, Marcela

AU - Rashid, Mamunur

AU - Speak, Anneliese O.

AU - Grinkevich, Vera

AU - Behan, Fiona

AU - Tamborero, David

AU - Iorio, Francesco

AU - van Dongen, Stijn

AU - Bignell, Graham R.

AU - Alsinet, Clara

AU - Chen, Sofia

AU - Supper, Emmanuelle

AU - Dutton-Regester, Ken

AU - Pritchard, Antonia

AU - Wong, Chi

AU - Enright, Anton

AU - Newton-Bishop, Julia

AU - McDermott, Ultan

AU - Hayward, Nicholas K.

AU - Choudhary, Jyoti S.

AU - Yusa, Kosuke

AU - Wessels, Lodewyk

AU - Garnett, Mathew J.

AU - Peeper, Daniel

AU - Adams, David J.

PY - 2017/9/28

Y1 - 2017/9/28

N2 - Despite recent therapeutic advances in the management of BRAFV600-mutant melanoma, there is still a compelling need for more effective treatments for patients who developed BRAF/NRAS wild type disease. Since the activity of single targeted agents is limited by innate and acquired resistance, we performed a high-throughput drug screen using 180 drug combinations to generate over 18,000 viability curves, with the aim of identifying agents that synergise to kill BRAF/NRAS wild type melanoma cells. From this screen we observed strong synergy between the tyrosine kinase inhibitor nilotinib and MEK inhibitors and validated this combination in an independent cell line collection. We found that AXL expression was associated with synergy to the nilotinib/MEK inhibitor combination, and that both drugs work in concert to suppress pERK. This finding was supported by genome-wide CRISPR screening which revealed that resistance mechanisms converge on regulators of the MAPK pathway. Finally, we validated the synergy of nilotinib/trametinib combination in vivo using patient-derived xenografts. Our results indicate that a nilotinib/MEK inhibitor combination may represent an effective therapy in BRAF/NRAS wild type melanoma patients.

AB - Despite recent therapeutic advances in the management of BRAFV600-mutant melanoma, there is still a compelling need for more effective treatments for patients who developed BRAF/NRAS wild type disease. Since the activity of single targeted agents is limited by innate and acquired resistance, we performed a high-throughput drug screen using 180 drug combinations to generate over 18,000 viability curves, with the aim of identifying agents that synergise to kill BRAF/NRAS wild type melanoma cells. From this screen we observed strong synergy between the tyrosine kinase inhibitor nilotinib and MEK inhibitors and validated this combination in an independent cell line collection. We found that AXL expression was associated with synergy to the nilotinib/MEK inhibitor combination, and that both drugs work in concert to suppress pERK. This finding was supported by genome-wide CRISPR screening which revealed that resistance mechanisms converge on regulators of the MAPK pathway. Finally, we validated the synergy of nilotinib/trametinib combination in vivo using patient-derived xenografts. Our results indicate that a nilotinib/MEK inhibitor combination may represent an effective therapy in BRAF/NRAS wild type melanoma patients.

U2 - 10.1101/195354

DO - 10.1101/195354

M3 - Preprint

BT - A screen for combination therapies in BRAF/NRAS wild type melanoma identifies nilotinib plus MEK inhibitor as a synergistic combination

PB - bioRxiv

ER -

A screen for combination therapies in BRAF/NRAS wild type melanoma identifies nilotinib plus MEK inhibitor as a synergistic combination

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