Quantitative Interrogation of the Human Kinome Perturbed by Two BRAF Inhibitors

Area of Science:

• Cancer Biology
• Proteomics
• Pharmacology

Background:

• Oncogenic BRAF mutations drive cancer development.
• FDA-approved BRAF inhibitors (dabrafenib, vemurafenib) are used in cancer therapy.
• Understanding drug-induced proteomic alterations is crucial for optimizing cancer treatment.

Purpose of the Study:

• To investigate the differential effects of dabrafenib and vemurafenib on protein expression and kinase ATP binding affinities in melanoma cells.
• To identify novel kinase targets affected by these BRAF inhibitors.

Main Methods:

• Employed targeted quantitative proteomics to monitor protein expression.
• Utilized quantitative proteomics to assess changes in kinase ATP binding affinities.
• Studied alterations in cultured human melanoma cells treated with dabrafenib and vemurafenib.

Main Results:

• Dabrafenib and vemurafenib induced markedly different reprograming of the human kinome.
• Vemurafenib was confirmed to compromise MAP2K5 ATP binding capacity and inhibit its kinase activity in cells.
• Profound changes in kinase protein expression levels were observed in melanoma cells upon treatment.

Conclusions:

• Targeted proteomic approaches revealed distinct cellular responses to clinically used BRAF inhibitors.
• The study identified novel putative target kinases for dabrafenib and vemurafenib.
• These findings enhance our understanding of BRAF inhibitor mechanisms and potential resistance pathways.