Illuminating oncogenic KRAS signaling by multi-dimensional chemical proteomics

Mutated KRAS is among the most frequent activating genetic alterations in cancer. Drug discovery efforts have led to inhibitors that block mutant KRAS activity. To better understand the molecular basis of their cytostatic rather than cytotoxic effects, we performed comprehensive dose-dependent proteome-wide target deconvolution, pathway engagement and protein expression characterization in response to KRAS, MEK, ERK, SHP2, and SOS1 inhibitors in pancreatic (KRAS G12C, G12D) and lung cancer (KRAS G12C) cell lines. Analysis of 688,716 dose-response curves available in ProteomicsDB revealed common and cell line-specific signaling networks dominated by KRAS activity. Time-dose experiments separated early ERK-driven from late CDK-mediated signaling leading to exit from the cell cycle. The transition occurred without substantial proteome re-modelling but extensive changes in phosphorylation and ubiquitinylation. Our resource highlights the complexity of KRAS signaling in cancer and places a large number of new proteins and their modifications into this functional context for further exploration.

Here, we provide all curve data processed with internal pipelines or CurveCurator v0.5.0. (https://github.com/kusterlab/curve_curator). All phospho proteome, whole proteome, ubiquitinome, and cysteine profiling data are in seperated zip folders. Within these folders, each subexperiment can be interactively reviewed. Next to each data set is the toml parameter file used to generate the curves.txt and dashboard.html files. The data structure and additional information separated by experiment is provided in the Meta file.