A Combination of Conformation-Specific RAF Inhibitors Overcome Drug Resistance Brought about by RAF Overexpression
Cancer cells often adapt to targeted therapies, yet the molecular mechanisms underlying adaptive resistance remain only partially understood. Here, we explore a mechanism of RAS/RAF/MEK/ERK (MAPK) pathway reactivation through the upregulation of RAF isoform (RAFs) abundance. Using computational mode...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-08-01
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| Series: | Biomolecules |
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| Online Access: | https://www.mdpi.com/2218-273X/13/8/1212 |
| _version_ | 1797585392249077760 |
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| author | Hiroaki Imoto Nora Rauch Ashish J. Neve Fahimeh Khorsand Martina Kreileder Leonidas G. Alexopoulos Jens Rauch Mariko Okada Boris N. Kholodenko Oleksii S. Rukhlenko |
| author_facet | Hiroaki Imoto Nora Rauch Ashish J. Neve Fahimeh Khorsand Martina Kreileder Leonidas G. Alexopoulos Jens Rauch Mariko Okada Boris N. Kholodenko Oleksii S. Rukhlenko |
| author_sort | Hiroaki Imoto |
| collection | DOAJ |
| description | Cancer cells often adapt to targeted therapies, yet the molecular mechanisms underlying adaptive resistance remain only partially understood. Here, we explore a mechanism of RAS/RAF/MEK/ERK (MAPK) pathway reactivation through the upregulation of RAF isoform (RAFs) abundance. Using computational modeling and in vitro experiments, we show that the upregulation of RAFs changes the concentration range of paradoxical pathway activation upon treatment with conformation-specific RAF inhibitors. Additionally, our data indicate that the signaling output upon loss or downregulation of one RAF isoform can be compensated by overexpression of other RAF isoforms. We furthermore demonstrate that, while single RAF inhibitors cannot efficiently inhibit ERK reactivation caused by RAF overexpression, a combination of two structurally distinct RAF inhibitors synergizes to robustly suppress pathway reactivation. |
| first_indexed | 2024-03-11T00:05:29Z |
| format | Article |
| id | doaj.art-7dcb85afd59b4b5ebacd96250fa08b80 |
| institution | Directory Open Access Journal |
| issn | 2218-273X |
| language | English |
| last_indexed | 2024-03-11T00:05:29Z |
| publishDate | 2023-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomolecules |
| spelling | doaj.art-7dcb85afd59b4b5ebacd96250fa08b802023-11-19T00:23:48ZengMDPI AGBiomolecules2218-273X2023-08-01138121210.3390/biom13081212A Combination of Conformation-Specific RAF Inhibitors Overcome Drug Resistance Brought about by RAF OverexpressionHiroaki Imoto0Nora Rauch1Ashish J. Neve2Fahimeh Khorsand3Martina Kreileder4Leonidas G. Alexopoulos5Jens Rauch6Mariko Okada7Boris N. Kholodenko8Oleksii S. Rukhlenko9Systems Biology Ireland, School of Medicine, University College Dublin, D04 V1W8 Dublin, IrelandSystems Biology Ireland, School of Medicine, University College Dublin, D04 V1W8 Dublin, IrelandSystems Biology Ireland, School of Medicine, University College Dublin, D04 V1W8 Dublin, IrelandSystems Biology Ireland, School of Medicine, University College Dublin, D04 V1W8 Dublin, IrelandSystems Biology Ireland, School of Medicine, University College Dublin, D04 V1W8 Dublin, IrelandProtavio Ltd., Demokritos Science Park, 153 43 Athens, GreeceSystems Biology Ireland, School of Medicine, University College Dublin, D04 V1W8 Dublin, IrelandInstitute for Protein Research, Osaka University, Osaka 565-0871, JapanSystems Biology Ireland, School of Medicine, University College Dublin, D04 V1W8 Dublin, IrelandSystems Biology Ireland, School of Medicine, University College Dublin, D04 V1W8 Dublin, IrelandCancer cells often adapt to targeted therapies, yet the molecular mechanisms underlying adaptive resistance remain only partially understood. Here, we explore a mechanism of RAS/RAF/MEK/ERK (MAPK) pathway reactivation through the upregulation of RAF isoform (RAFs) abundance. Using computational modeling and in vitro experiments, we show that the upregulation of RAFs changes the concentration range of paradoxical pathway activation upon treatment with conformation-specific RAF inhibitors. Additionally, our data indicate that the signaling output upon loss or downregulation of one RAF isoform can be compensated by overexpression of other RAF isoforms. We furthermore demonstrate that, while single RAF inhibitors cannot efficiently inhibit ERK reactivation caused by RAF overexpression, a combination of two structurally distinct RAF inhibitors synergizes to robustly suppress pathway reactivation.https://www.mdpi.com/2218-273X/13/8/1212MAP KinasesRAF dimerizationRAF inhibitor resistancestructure-based mechanistic modelingRAF isoformsARAF knockout |
| spellingShingle | Hiroaki Imoto Nora Rauch Ashish J. Neve Fahimeh Khorsand Martina Kreileder Leonidas G. Alexopoulos Jens Rauch Mariko Okada Boris N. Kholodenko Oleksii S. Rukhlenko A Combination of Conformation-Specific RAF Inhibitors Overcome Drug Resistance Brought about by RAF Overexpression Biomolecules MAP Kinases RAF dimerization RAF inhibitor resistance structure-based mechanistic modeling RAF isoforms ARAF knockout |
| title | A Combination of Conformation-Specific RAF Inhibitors Overcome Drug Resistance Brought about by RAF Overexpression |
| title_full | A Combination of Conformation-Specific RAF Inhibitors Overcome Drug Resistance Brought about by RAF Overexpression |
| title_fullStr | A Combination of Conformation-Specific RAF Inhibitors Overcome Drug Resistance Brought about by RAF Overexpression |
| title_full_unstemmed | A Combination of Conformation-Specific RAF Inhibitors Overcome Drug Resistance Brought about by RAF Overexpression |
| title_short | A Combination of Conformation-Specific RAF Inhibitors Overcome Drug Resistance Brought about by RAF Overexpression |
| title_sort | combination of conformation specific raf inhibitors overcome drug resistance brought about by raf overexpression |
| topic | MAP Kinases RAF dimerization RAF inhibitor resistance structure-based mechanistic modeling RAF isoforms ARAF knockout |
| url | https://www.mdpi.com/2218-273X/13/8/1212 |
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