Pan-RAF and MEK vertical inhibition enhances therapeutic response in non-V600 BRAF mutant cells

Eszter Molnár, Dominika Rittler, Marcell Baranyi, Michael Grusch, Walter Berger, B. Döme, J. Tóvári, Clemens Aigner, J. Tímár, Tamás Garay, Balázs Hegedus

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Abstract

Background: Currently, there are no available targeted therapy options for non-V600 BRAF mutated tumors. The aim of this study was to investigate the effects of RAF and MEK concurrent inhibition on tumor growth, migration, signaling and apoptosis induction in preclinical models of non-V600 BRAF mutant tumor cell lines. Methods: Six BRAF mutated human tumor cell lines CRL5885 (G466 V), WM3629 (D594G), WM3670 (G469E), MDAMB231 (G464 V), CRL5922 (L597 V) and A375 (V600E as control) were investigated. Pan-RAF inhibitor (sorafenib or AZ628) and MEK inhibitor (selumetinib) or their combination were used in in vitro viability, video microscopy, immunoblot, cell cycle and TUNEL assays. The in vivo effects of the drugs were assessed in an orthotopic NSG mouse breast cancer model. Results: All cell lines showed a significant growth inhibition with synergism in the sorafenib/AZ628 and selumetinib combination. Combination treatment resulted in higher Erk1/2 inhibition and in increased induction of apoptosis when compared to single agent treatments. However, single selumetinib treatment could cause adverse therapeutic effects, like increased cell migration in certain cells, selumetinib and sorafenib combination treatment lowered migratory capacity in all the cell lines. Importantly, combination resulted in significantly increased tumor growth inhibition in orthotropic xenografts of MDAMB231 cells when compared to sorafenib - but not to selumetinib - treatment. Conclusions: Our data suggests that combined blocking of RAF and MEK may achieve increased therapeutic response in non-V600 BRAF mutant tumors.

Original languageEnglish
Article number542
JournalBMC Cancer
Volume18
Issue number1
DOIs
Publication statusPublished - May 8 2018

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Mitogen-Activated Protein Kinase Kinases
Tumor Cell Line
Neoplasms
Growth
Apoptosis
Therapeutics
Cell Line
Video Microscopy
In Situ Nick-End Labeling
Therapeutic Uses
Heterografts
Cell Movement
Cell Cycle
AZD 6244
Breast Neoplasms
sorafenib
Pharmaceutical Preparations

Keywords

  • Apoptosis
  • AZ628
  • Inhibition
  • MEK
  • Migration
  • Non-V600 BRAF mutation
  • Proliferation
  • RAF
  • Selumetinib
  • Sorafenib

ASJC Scopus subject areas

  • Oncology
  • Genetics
  • Cancer Research

Cite this

Molnár, E., Rittler, D., Baranyi, M., Grusch, M., Berger, W., Döme, B., ... Hegedus, B. (2018). Pan-RAF and MEK vertical inhibition enhances therapeutic response in non-V600 BRAF mutant cells. BMC Cancer, 18(1), [542]. https://doi.org/10.1186/s12885-018-4455-x

Pan-RAF and MEK vertical inhibition enhances therapeutic response in non-V600 BRAF mutant cells. / Molnár, Eszter; Rittler, Dominika; Baranyi, Marcell; Grusch, Michael; Berger, Walter; Döme, B.; Tóvári, J.; Aigner, Clemens; Tímár, J.; Garay, Tamás; Hegedus, Balázs.

In: BMC Cancer, Vol. 18, No. 1, 542, 08.05.2018.

Research output: Contribution to journalArticle

Molnár, E, Rittler, D, Baranyi, M, Grusch, M, Berger, W, Döme, B, Tóvári, J, Aigner, C, Tímár, J, Garay, T & Hegedus, B 2018, 'Pan-RAF and MEK vertical inhibition enhances therapeutic response in non-V600 BRAF mutant cells', BMC Cancer, vol. 18, no. 1, 542. https://doi.org/10.1186/s12885-018-4455-x
Molnár, Eszter ; Rittler, Dominika ; Baranyi, Marcell ; Grusch, Michael ; Berger, Walter ; Döme, B. ; Tóvári, J. ; Aigner, Clemens ; Tímár, J. ; Garay, Tamás ; Hegedus, Balázs. / Pan-RAF and MEK vertical inhibition enhances therapeutic response in non-V600 BRAF mutant cells. In: BMC Cancer. 2018 ; Vol. 18, No. 1.
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AU - Baranyi, Marcell

AU - Grusch, Michael

AU - Berger, Walter

AU - Döme, B.

AU - Tóvári, J.

AU - Aigner, Clemens

AU - Tímár, J.

AU - Garay, Tamás

AU - Hegedus, Balázs

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