Proteomic Mapping of the Interactome of KRAS Mutants Identifies New Features of RAS Signalling Networks and the Mechanism of Action of Sotorasib
RAS proteins are key regulators of cell signalling and control different cell functions including cell proliferation, differentiation, and cell death. Point mutations in the genes of this family are common, particularly in <i>KRAS</i>. These mutations were thought to cause the constituti...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-08-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/15/16/4141 |
| _version_ | 1797585222505594880 |
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| author | Aoife Nolan Cinzia Raso Walter Kolch Alex von Kriegsheim Kieran Wynne David Matallanas |
| author_facet | Aoife Nolan Cinzia Raso Walter Kolch Alex von Kriegsheim Kieran Wynne David Matallanas |
| author_sort | Aoife Nolan |
| collection | DOAJ |
| description | RAS proteins are key regulators of cell signalling and control different cell functions including cell proliferation, differentiation, and cell death. Point mutations in the genes of this family are common, particularly in <i>KRAS</i>. These mutations were thought to cause the constitutive activation of KRAS, but recent findings showed that some mutants can cycle between active and inactive states. This observation, together with the development of covalent KRASG12C inhibitors, has led to the arrival of KRAS inhibitors in the clinic. However, most patients develop resistance to these targeted therapies, and we lack effective treatments for other KRAS mutants. To accelerate the development of RAS targeting therapies, we need to fully characterise the molecular mechanisms governing KRAS signalling networks and determine what differentiates the signalling downstream of the KRAS mutants. Here we have used affinity purification mass-spectrometry proteomics to characterise the interactome of KRAS wild-type and three KRAS mutants. Bioinformatic analysis associated with experimental validation allows us to map the signalling network mediated by the different KRAS proteins. Using this approach, we characterised how the interactome of KRAS wild-type and mutants is regulated by the clinically approved KRASG12C inhibitor Sotorasib. In addition, we identified novel crosstalks between KRAS and its effector pathways including the AKT and JAK-STAT signalling modules. |
| first_indexed | 2024-03-11T00:03:01Z |
| format | Article |
| id | doaj.art-11d761a8e36c4b76ac20ffc4ac6ef66e |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-11T00:03:01Z |
| publishDate | 2023-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-11d761a8e36c4b76ac20ffc4ac6ef66e2023-11-19T00:33:51ZengMDPI AGCancers2072-66942023-08-011516414110.3390/cancers15164141Proteomic Mapping of the Interactome of KRAS Mutants Identifies New Features of RAS Signalling Networks and the Mechanism of Action of SotorasibAoife Nolan0Cinzia Raso1Walter Kolch2Alex von Kriegsheim3Kieran Wynne4David Matallanas5Systems Biology Ireland, School of Medicine, University College Dublin, Belfield, D04 V1W8 Dublin, IrelandSystems Biology Ireland, School of Medicine, University College Dublin, Belfield, D04 V1W8 Dublin, IrelandSystems Biology Ireland, School of Medicine, University College Dublin, Belfield, D04 V1W8 Dublin, IrelandSystems Biology Ireland, School of Medicine, University College Dublin, Belfield, D04 V1W8 Dublin, IrelandSystems Biology Ireland, School of Medicine, University College Dublin, Belfield, D04 V1W8 Dublin, IrelandSystems Biology Ireland, School of Medicine, University College Dublin, Belfield, D04 V1W8 Dublin, IrelandRAS proteins are key regulators of cell signalling and control different cell functions including cell proliferation, differentiation, and cell death. Point mutations in the genes of this family are common, particularly in <i>KRAS</i>. These mutations were thought to cause the constitutive activation of KRAS, but recent findings showed that some mutants can cycle between active and inactive states. This observation, together with the development of covalent KRASG12C inhibitors, has led to the arrival of KRAS inhibitors in the clinic. However, most patients develop resistance to these targeted therapies, and we lack effective treatments for other KRAS mutants. To accelerate the development of RAS targeting therapies, we need to fully characterise the molecular mechanisms governing KRAS signalling networks and determine what differentiates the signalling downstream of the KRAS mutants. Here we have used affinity purification mass-spectrometry proteomics to characterise the interactome of KRAS wild-type and three KRAS mutants. Bioinformatic analysis associated with experimental validation allows us to map the signalling network mediated by the different KRAS proteins. Using this approach, we characterised how the interactome of KRAS wild-type and mutants is regulated by the clinically approved KRASG12C inhibitor Sotorasib. In addition, we identified novel crosstalks between KRAS and its effector pathways including the AKT and JAK-STAT signalling modules.https://www.mdpi.com/2072-6694/15/16/4141KRASproteomicsJAK1RADILSotorasibSOS1 |
| spellingShingle | Aoife Nolan Cinzia Raso Walter Kolch Alex von Kriegsheim Kieran Wynne David Matallanas Proteomic Mapping of the Interactome of KRAS Mutants Identifies New Features of RAS Signalling Networks and the Mechanism of Action of Sotorasib Cancers KRAS proteomics JAK1 RADIL Sotorasib SOS1 |
| title | Proteomic Mapping of the Interactome of KRAS Mutants Identifies New Features of RAS Signalling Networks and the Mechanism of Action of Sotorasib |
| title_full | Proteomic Mapping of the Interactome of KRAS Mutants Identifies New Features of RAS Signalling Networks and the Mechanism of Action of Sotorasib |
| title_fullStr | Proteomic Mapping of the Interactome of KRAS Mutants Identifies New Features of RAS Signalling Networks and the Mechanism of Action of Sotorasib |
| title_full_unstemmed | Proteomic Mapping of the Interactome of KRAS Mutants Identifies New Features of RAS Signalling Networks and the Mechanism of Action of Sotorasib |
| title_short | Proteomic Mapping of the Interactome of KRAS Mutants Identifies New Features of RAS Signalling Networks and the Mechanism of Action of Sotorasib |
| title_sort | proteomic mapping of the interactome of kras mutants identifies new features of ras signalling networks and the mechanism of action of sotorasib |
| topic | KRAS proteomics JAK1 RADIL Sotorasib SOS1 |
| url | https://www.mdpi.com/2072-6694/15/16/4141 |
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