Tumor-specific Kinase Motif Enrichment Analysis Identifies Personalized Therapeutic Cancer Targets

Area of Science:

• Oncology
• Biochemistry
• Molecular Biology

Background:

• Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are rare malignancies with low mutation burden and unclear drivers.
• Hepatic metastases are a common cause of mortality in GEP-NET patients.
• Standard genomic and transcriptomic methods often fail to identify actionable targets in GEP-NETs.

Purpose of the Study:

• To identify tumor-specific signaling pathways and vulnerabilities in GEP-NET liver metastases.
• To explore the utility of Kinase Motif Enrichment Analysis (KMEA) for personalized cancer treatment.

Main Methods:

• Phosphoproteomic data from GEP-NET liver metastases and matched normal liver tissue were analyzed.
• Kinase Motif Enrichment Analysis (KMEA) was employed using the Kinase Library compendium.
• Patient tumor-derived organoids were used to test sensitivity to kinase inhibitors.

Main Results:

• KMEA revealed patient-specific upregulation of mTOR or CK2 activity in GEP-NET liver metastases.
• These kinase activities were not apparent through standard genomic or transcriptomic analyses.
• Organoid models showed concordance between KMEA predictions and sensitivity to mTOR or CK2 inhibitors.

Conclusions:

• Hyperactivated protein kinases, specifically mTOR and CK2, represent potential therapeutic targets in GEP-NETs.
• Phosphoproteomics combined with KMEA offers a novel approach for personalized cancer therapy.
• This methodology can uncover clinically actionable kinase targets in cancers with low mutational burden.