Proteomic analyses identify targets, pathways, and cellular consequences of oncogenic KRAS signaling

Area of Science:

• Oncology
• Molecular Biology
• Cancer Genomics

Background:

• Activating mutations in the small GTPase KRAS are common drivers in many cancers.
• Drug discovery has yielded inhibitors targeting KRAS activity and its downstream signaling pathways.
• Understanding the precise effects of these inhibitors is crucial for effective cancer therapy.

Purpose of the Study:

• To investigate oncogenic KRAS signaling in response to targeted inhibitors.
• To elucidate the cytostatic effects and molecular mechanisms of KRAS-targeted drugs.
• To identify changes in protein abundance and posttranslational modifications in response to treatment.

Main Methods:

• Proteomic analyses, including phosphoproteomics, were performed on human KRAS-mutant pancreatic and lung cancer cell lines.
• Cells were treated with inhibitors targeting KRAS, MEK, ERK, SHP2, and SOS1.
• Comparisons of phosphoproteomes were made after short and long drug exposures to analyze temporal dynamics.

Main Results:

• A core KRAS signaling signature and cell line-specific networks were identified.
• Autonomous, oncogenic KRAS activity dominated phosphoproteomes across cell lines.
• Inhibition of the KRAS-MEK-ERK axis led to cell cycle exit, characterized by broad phosphorylation and ubiquitylation changes without significant proteome remodeling.

Conclusions:

• KRAS-targeted therapies induce cell cycle exit, a mechanism for evading cell death.
• Proteomic insights reveal the temporal dynamics of pathway inhibition and its impact on cellular state.
• The study identifies additional proteins involved in oncogenic KRAS signaling and its inhibition.