Proteomic mapping of the interactome of KRAS mutants identifies new features of RAS signalling networks and the mechanism of action of Sotorasib.

ABSTRACT: RAS proteins are key regulators of cell signalling and are master regulators of different cell functions including cell proliferation, differentiation and cell death. Point mutations in the genes of this family are common, particularly in the KRAS. These mutations were thought to cause the constative activation of KRAS, but recent findings showed that some of these mutants can still cycle between active and inactive states. This observation together with the development of covalent KRASG12C inhibitors has led to the arrival to the clinic of KRAS inhibitors. However, most patients develop resistance to these targeted therapies, and we still lack effective treatments for other KRAS mutants. In order to accelerate the development of RAS targeting therapies we need to complete our characterisation of the molecular mechanisms that govern KRAS signalling networks and in particular determine if there are differences among the different 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 allow us to map the signalling network mediated by the different KRAS proteins. Using this approach, we have also characterised the effect that clinically approved KRASG12 inhibitor sotorasib has in the interactome of these mutants and KRAS wild type. Our work indicates that this drug regulates the interactome and identifies new crosstalks between KRAS and its effector pathways including the AKT and JAK-STAT signalling modules.

INSTRUMENT(S): timsTOF Pro

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Early Embryonic Cell, Kidney

DISEASE(S): Kidney Cancer

SUBMITTER: Kieran Wynne  

LAB HEAD: David Gomez

PROVIDER: PXD043536 | Pride | 2023-10-15

REPOSITORIES: Pride