Preclinical assessment of MEK1/2 inhibitors for neurofibromatosis type 2-associated schwannomas reveals differences in efficacy and drug resistance development

Marisa A. Fuse, Christine T Dinh, Jeremie Vitte, Joanna Kirkpatrick, Thomas Mindos, Stephani Klingeman Plati, Juan Young, Jie Huang, Annemarie Carlstedt, Maria Clara Franco, Konstantin Brnjos, Jackson Nagamoto, Alejandra M. Petrilli, Alicja J. Copik, Julia N. Soulakova, Olena Bracho, Denise Yan, Rahul Mittal, Rulong Shen, Fred F TelischiHelen Morrison, Marco Giovannini, Xue Z Liu, Long Sheng Chang, Cristina Fernandez-Valle

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Background. Neurofibromatosis type 2 (NF2) is a genetic tumor-predisposition disorder caused by NF2/merlin tumor suppressor gene inactivation. The hallmark of NF2 is formation of bilateral vestibular schwannomas (VS). Because merlin modulates activity of the Ras/Raf/mitogen-activated protein kinase kinase (MEK)/extracellular signal- regulated kinase (ERK) pathway, we investigated repurposing drugs targeting MEK1 and/or MEK2 as a treatment for NF2-associated schwannomas. Methods. Mouse and human merlin-deficient Schwann cell lines (MD-MSC/HSC) were screened against 6 MEK1/2 inhibitors. Efficacious drugs were tested in orthotopic allograft and NF2 transgenic mouse models. Pathway and proteome analyses were conducted. Drug efficacy was examined in primary human VS cells with NF2 mutations and correlated with DNA methylation patterns. Results. Trametinib, PD0325901, and cobimetinib were most effective in reducing MD-MSC/HSC viability. Each decreased phosphorylated pERK1/2 and cyclin D1, increased p27, and induced caspase-3 cleavage in MD-MSCs. Proteomic analysis confirmed cell cycle arrest and activation of pro-apoptotic pathways in trametinib-treated MD-MSCs. The 3 inhibitors slowed allograft growth; however, decreased pERK1/2, cyclin D1, and Ki-67 levels were observed only in PD0325901 and cobimetinib-treated grafts. Tumor burden and average tumor size were reduced in trametinib-treated NF2 transgenic mice; however, tumors did not exhibit reduced pERK1/2 levels. Trametinib and PD0325901 modestly reduced viability of several primary human VS cell cultures with NF2 mutations. DNA methylation analysis of PD0325901-resistant versus -susceptible VS identified genes that could contribute to drug resistance. Conclusion. MEK inhibitors exhibited differences in antitumor efficacy resistance in schwannoma models with possible emergence of trametinib resistance. The results support further investigation of MEK inhibitors in combination with other targeted drugs for NF2 schwannomas.

Original languageEnglish (US)
Pages (from-to)486-497
Number of pages12
JournalNeuro-Oncology
Volume21
Issue number4
DOIs
StatePublished - Mar 18 2019

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Neurofibromatosis 2
Neurilemmoma
Drug Resistance
Acoustic Neuroma
Neurofibromin 2
Mitogen-Activated Protein Kinase Kinases
Cyclin D1
DNA Methylation
Transgenic Mice
Allografts
Pharmaceutical Preparations
Neoplasms
Mutation
Schwann Cells
Extracellular Signal-Regulated MAP Kinases
Gene Silencing
Proteome
Drug Delivery Systems
Genetic Predisposition to Disease
Cell Cycle Checkpoints

Keywords

  • MEK inhibitors
  • merlin tumor suppressor
  • methylome
  • NF2 transgenic mice
  • patient-derived vestibular schwannomas

ASJC Scopus subject areas

  • Oncology
  • Clinical Neurology
  • Cancer Research

Cite this

Preclinical assessment of MEK1/2 inhibitors for neurofibromatosis type 2-associated schwannomas reveals differences in efficacy and drug resistance development. / Fuse, Marisa A.; Dinh, Christine T; Vitte, Jeremie; Kirkpatrick, Joanna; Mindos, Thomas; Plati, Stephani Klingeman; Young, Juan; Huang, Jie; Carlstedt, Annemarie; Franco, Maria Clara; Brnjos, Konstantin; Nagamoto, Jackson; Petrilli, Alejandra M.; Copik, Alicja J.; Soulakova, Julia N.; Bracho, Olena; Yan, Denise; Mittal, Rahul; Shen, Rulong; Telischi, Fred F; Morrison, Helen; Giovannini, Marco; Liu, Xue Z; Chang, Long Sheng; Fernandez-Valle, Cristina.

In: Neuro-Oncology, Vol. 21, No. 4, 18.03.2019, p. 486-497.

Research output: Contribution to journalArticle

Fuse, MA, Dinh, CT, Vitte, J, Kirkpatrick, J, Mindos, T, Plati, SK, Young, J, Huang, J, Carlstedt, A, Franco, MC, Brnjos, K, Nagamoto, J, Petrilli, AM, Copik, AJ, Soulakova, JN, Bracho, O, Yan, D, Mittal, R, Shen, R, Telischi, FF, Morrison, H, Giovannini, M, Liu, XZ, Chang, LS & Fernandez-Valle, C 2019, 'Preclinical assessment of MEK1/2 inhibitors for neurofibromatosis type 2-associated schwannomas reveals differences in efficacy and drug resistance development', Neuro-Oncology, vol. 21, no. 4, pp. 486-497. https://doi.org/10.1093/neuonc/noz002
Fuse, Marisa A. ; Dinh, Christine T ; Vitte, Jeremie ; Kirkpatrick, Joanna ; Mindos, Thomas ; Plati, Stephani Klingeman ; Young, Juan ; Huang, Jie ; Carlstedt, Annemarie ; Franco, Maria Clara ; Brnjos, Konstantin ; Nagamoto, Jackson ; Petrilli, Alejandra M. ; Copik, Alicja J. ; Soulakova, Julia N. ; Bracho, Olena ; Yan, Denise ; Mittal, Rahul ; Shen, Rulong ; Telischi, Fred F ; Morrison, Helen ; Giovannini, Marco ; Liu, Xue Z ; Chang, Long Sheng ; Fernandez-Valle, Cristina. / Preclinical assessment of MEK1/2 inhibitors for neurofibromatosis type 2-associated schwannomas reveals differences in efficacy and drug resistance development. In: Neuro-Oncology. 2019 ; Vol. 21, No. 4. pp. 486-497.
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abstract = "Background. Neurofibromatosis type 2 (NF2) is a genetic tumor-predisposition disorder caused by NF2/merlin tumor suppressor gene inactivation. The hallmark of NF2 is formation of bilateral vestibular schwannomas (VS). Because merlin modulates activity of the Ras/Raf/mitogen-activated protein kinase kinase (MEK)/extracellular signal- regulated kinase (ERK) pathway, we investigated repurposing drugs targeting MEK1 and/or MEK2 as a treatment for NF2-associated schwannomas. Methods. Mouse and human merlin-deficient Schwann cell lines (MD-MSC/HSC) were screened against 6 MEK1/2 inhibitors. Efficacious drugs were tested in orthotopic allograft and NF2 transgenic mouse models. Pathway and proteome analyses were conducted. Drug efficacy was examined in primary human VS cells with NF2 mutations and correlated with DNA methylation patterns. Results. Trametinib, PD0325901, and cobimetinib were most effective in reducing MD-MSC/HSC viability. Each decreased phosphorylated pERK1/2 and cyclin D1, increased p27, and induced caspase-3 cleavage in MD-MSCs. Proteomic analysis confirmed cell cycle arrest and activation of pro-apoptotic pathways in trametinib-treated MD-MSCs. The 3 inhibitors slowed allograft growth; however, decreased pERK1/2, cyclin D1, and Ki-67 levels were observed only in PD0325901 and cobimetinib-treated grafts. Tumor burden and average tumor size were reduced in trametinib-treated NF2 transgenic mice; however, tumors did not exhibit reduced pERK1/2 levels. Trametinib and PD0325901 modestly reduced viability of several primary human VS cell cultures with NF2 mutations. DNA methylation analysis of PD0325901-resistant versus -susceptible VS identified genes that could contribute to drug resistance. Conclusion. MEK inhibitors exhibited differences in antitumor efficacy resistance in schwannoma models with possible emergence of trametinib resistance. The results support further investigation of MEK inhibitors in combination with other targeted drugs for NF2 schwannomas.",
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author = "Fuse, {Marisa A.} and Dinh, {Christine T} and Jeremie Vitte and Joanna Kirkpatrick and Thomas Mindos and Plati, {Stephani Klingeman} and Juan Young and Jie Huang and Annemarie Carlstedt and Franco, {Maria Clara} and Konstantin Brnjos and Jackson Nagamoto and Petrilli, {Alejandra M.} and Copik, {Alicja J.} and Soulakova, {Julia N.} and Olena Bracho and Denise Yan and Rahul Mittal and Rulong Shen and Telischi, {Fred F} and Helen Morrison and Marco Giovannini and Liu, {Xue Z} and Chang, {Long Sheng} and Cristina Fernandez-Valle",
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TY - JOUR

T1 - Preclinical assessment of MEK1/2 inhibitors for neurofibromatosis type 2-associated schwannomas reveals differences in efficacy and drug resistance development

AU - Fuse, Marisa A.

AU - Dinh, Christine T

AU - Vitte, Jeremie

AU - Kirkpatrick, Joanna

AU - Mindos, Thomas

AU - Plati, Stephani Klingeman

AU - Young, Juan

AU - Huang, Jie

AU - Carlstedt, Annemarie

AU - Franco, Maria Clara

AU - Brnjos, Konstantin

AU - Nagamoto, Jackson

AU - Petrilli, Alejandra M.

AU - Copik, Alicja J.

AU - Soulakova, Julia N.

AU - Bracho, Olena

AU - Yan, Denise

AU - Mittal, Rahul

AU - Shen, Rulong

AU - Telischi, Fred F

AU - Morrison, Helen

AU - Giovannini, Marco

AU - Liu, Xue Z

AU - Chang, Long Sheng

AU - Fernandez-Valle, Cristina

PY - 2019/3/18

Y1 - 2019/3/18

N2 - Background. Neurofibromatosis type 2 (NF2) is a genetic tumor-predisposition disorder caused by NF2/merlin tumor suppressor gene inactivation. The hallmark of NF2 is formation of bilateral vestibular schwannomas (VS). Because merlin modulates activity of the Ras/Raf/mitogen-activated protein kinase kinase (MEK)/extracellular signal- regulated kinase (ERK) pathway, we investigated repurposing drugs targeting MEK1 and/or MEK2 as a treatment for NF2-associated schwannomas. Methods. Mouse and human merlin-deficient Schwann cell lines (MD-MSC/HSC) were screened against 6 MEK1/2 inhibitors. Efficacious drugs were tested in orthotopic allograft and NF2 transgenic mouse models. Pathway and proteome analyses were conducted. Drug efficacy was examined in primary human VS cells with NF2 mutations and correlated with DNA methylation patterns. Results. Trametinib, PD0325901, and cobimetinib were most effective in reducing MD-MSC/HSC viability. Each decreased phosphorylated pERK1/2 and cyclin D1, increased p27, and induced caspase-3 cleavage in MD-MSCs. Proteomic analysis confirmed cell cycle arrest and activation of pro-apoptotic pathways in trametinib-treated MD-MSCs. The 3 inhibitors slowed allograft growth; however, decreased pERK1/2, cyclin D1, and Ki-67 levels were observed only in PD0325901 and cobimetinib-treated grafts. Tumor burden and average tumor size were reduced in trametinib-treated NF2 transgenic mice; however, tumors did not exhibit reduced pERK1/2 levels. Trametinib and PD0325901 modestly reduced viability of several primary human VS cell cultures with NF2 mutations. DNA methylation analysis of PD0325901-resistant versus -susceptible VS identified genes that could contribute to drug resistance. Conclusion. MEK inhibitors exhibited differences in antitumor efficacy resistance in schwannoma models with possible emergence of trametinib resistance. The results support further investigation of MEK inhibitors in combination with other targeted drugs for NF2 schwannomas.

AB - Background. Neurofibromatosis type 2 (NF2) is a genetic tumor-predisposition disorder caused by NF2/merlin tumor suppressor gene inactivation. The hallmark of NF2 is formation of bilateral vestibular schwannomas (VS). Because merlin modulates activity of the Ras/Raf/mitogen-activated protein kinase kinase (MEK)/extracellular signal- regulated kinase (ERK) pathway, we investigated repurposing drugs targeting MEK1 and/or MEK2 as a treatment for NF2-associated schwannomas. Methods. Mouse and human merlin-deficient Schwann cell lines (MD-MSC/HSC) were screened against 6 MEK1/2 inhibitors. Efficacious drugs were tested in orthotopic allograft and NF2 transgenic mouse models. Pathway and proteome analyses were conducted. Drug efficacy was examined in primary human VS cells with NF2 mutations and correlated with DNA methylation patterns. Results. Trametinib, PD0325901, and cobimetinib were most effective in reducing MD-MSC/HSC viability. Each decreased phosphorylated pERK1/2 and cyclin D1, increased p27, and induced caspase-3 cleavage in MD-MSCs. Proteomic analysis confirmed cell cycle arrest and activation of pro-apoptotic pathways in trametinib-treated MD-MSCs. The 3 inhibitors slowed allograft growth; however, decreased pERK1/2, cyclin D1, and Ki-67 levels were observed only in PD0325901 and cobimetinib-treated grafts. Tumor burden and average tumor size were reduced in trametinib-treated NF2 transgenic mice; however, tumors did not exhibit reduced pERK1/2 levels. Trametinib and PD0325901 modestly reduced viability of several primary human VS cell cultures with NF2 mutations. DNA methylation analysis of PD0325901-resistant versus -susceptible VS identified genes that could contribute to drug resistance. Conclusion. MEK inhibitors exhibited differences in antitumor efficacy resistance in schwannoma models with possible emergence of trametinib resistance. The results support further investigation of MEK inhibitors in combination with other targeted drugs for NF2 schwannomas.

KW - MEK inhibitors

KW - merlin tumor suppressor

KW - methylome

KW - NF2 transgenic mice

KW - patient-derived vestibular schwannomas

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DO - 10.1093/neuonc/noz002

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