Pan-RAF and MEK vertical inhibition enhances therapeutic response in non-V600 BRAF mutant cells
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 B...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2018-05-01
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| Series: | BMC Cancer |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s12885-018-4455-x |
| _version_ | 1818545855937904640 |
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| author | Eszter Molnár Dominika Rittler Marcell Baranyi Michael Grusch Walter Berger Balázs Döme József Tóvári Clemens Aigner József Tímár Tamás Garay Balázs Hegedűs |
| author_facet | Eszter Molnár Dominika Rittler Marcell Baranyi Michael Grusch Walter Berger Balázs Döme József Tóvári Clemens Aigner József Tímár Tamás Garay Balázs Hegedűs |
| author_sort | Eszter Molnár |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-12T07:45:28Z |
| format | Article |
| id | doaj.art-eb03ce1342774897b38a56b7e9cee8a9 |
| institution | Directory Open Access Journal |
| issn | 1471-2407 |
| language | English |
| last_indexed | 2024-12-12T07:45:28Z |
| publishDate | 2018-05-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Cancer |
| spelling | doaj.art-eb03ce1342774897b38a56b7e9cee8a92022-12-22T00:32:38ZengBMCBMC Cancer1471-24072018-05-0118111110.1186/s12885-018-4455-xPan-RAF and MEK vertical inhibition enhances therapeutic response in non-V600 BRAF mutant cellsEszter Molnár0Dominika Rittler1Marcell Baranyi2Michael Grusch3Walter Berger4Balázs Döme5József Tóvári6Clemens Aigner7József Tímár8Tamás Garay9Balázs Hegedűs102nd Department of Pathology, Semmelweis University2nd Department of Pathology, Semmelweis University2nd Department of Pathology, Semmelweis UniversityInstitute of Cancer Research, Medical University of ViennaInstitute of Cancer Research, Medical University of ViennaDepartment of Thoracic Surgery, Medical University of ViennaDepartment of Experimental Pharmacology, National Institute of OncologyDepartment of Thoracic Surgery, Ruhrlandklinik, University Duisburg-Essen2nd Department of Pathology, Semmelweis University2nd Department of Pathology, Semmelweis University2nd Department of Pathology, Semmelweis UniversityAbstract 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.http://link.springer.com/article/10.1186/s12885-018-4455-xNon-V600 BRAF mutationSorafenibAZ628SelumetinibApoptosisProliferation |
| spellingShingle | Eszter Molnár Dominika Rittler Marcell Baranyi Michael Grusch Walter Berger Balázs Döme József Tóvári Clemens Aigner József Tímár Tamás Garay Balázs Hegedűs Pan-RAF and MEK vertical inhibition enhances therapeutic response in non-V600 BRAF mutant cells BMC Cancer Non-V600 BRAF mutation Sorafenib AZ628 Selumetinib Apoptosis Proliferation |
| title | Pan-RAF and MEK vertical inhibition enhances therapeutic response in non-V600 BRAF mutant cells |
| title_full | Pan-RAF and MEK vertical inhibition enhances therapeutic response in non-V600 BRAF mutant cells |
| title_fullStr | Pan-RAF and MEK vertical inhibition enhances therapeutic response in non-V600 BRAF mutant cells |
| title_full_unstemmed | Pan-RAF and MEK vertical inhibition enhances therapeutic response in non-V600 BRAF mutant cells |
| title_short | Pan-RAF and MEK vertical inhibition enhances therapeutic response in non-V600 BRAF mutant cells |
| title_sort | pan raf and mek vertical inhibition enhances therapeutic response in non v600 braf mutant cells |
| topic | Non-V600 BRAF mutation Sorafenib AZ628 Selumetinib Apoptosis Proliferation |
| url | http://link.springer.com/article/10.1186/s12885-018-4455-x |
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