Deciphering MET-dependent modulation of global cellular responses to DNA damage by quantitative phosphoproteomics

Area of Science:

• Oncology
• Molecular Biology
• Cancer Signaling

Background:

• Growth factor receptor tyrosine kinase (RTK) signaling interference affects DNA damage response (DDR) networks, influencing cancer treatment efficacy.
• The MET RTK is frequently deregulated in various human tumors, highlighting its role in cancer progression.

Purpose of the Study:

• To investigate how disrupting MET RTK signaling modulates the global cellular phosphorylation response to ionizing radiation (IR).
• To identify and characterize specific phosphorylation sites at the intersection of MET signaling and DDR networks.

Main Methods:

• Utilized two proteomic techniques: immunoaffinity-based phosphoproteomic discovery and targeted proteomics.
• Investigated phosphorylation site modulation following MET inhibition alone and in combination with IR.
• Validated key phosphorylation changes in vivo using immunohistochemistry in tumor models.

Main Results:

• Several DDR substrates were confirmed to be modulated by MET inhibition and/or IR.
• Specific phosphorylation changes were observed in NUMA1 S395 (gain) and CHEK1 S345 (loss) upon combined treatment.
• These findings were recapitulated in vivo, suggesting translational potential.

Conclusions:

• Corroborated specific phosphorylation sites at the intersection of MET and DDR signaling networks.
• Identified proteins that bridge oncogene-driven proliferation and genomic stability.
• Suggests potential therapeutic strategies targeting the MET-DDR axis in cancer treatment.