KinaseMD: kinase mutations and drug response database

Area of Science:

• Biochemistry and Molecular Biology
• Genomics and Bioinformatics
• Pharmacology and Drug Discovery

Background:

• Somatic mutations in kinase genes are prevalent in human diseases, particularly cancer, influencing signaling pathways and drug responses.
• Understanding kinase mutations is crucial for predicting drug sensitivity and resistance to kinase inhibitors.
• Existing resources lack comprehensive structural and functional annotations linking kinase mutations to drug response.

Purpose of the Study:

• To introduce KinaseMD, a novel database for the structural and functional annotation of kinase mutations and their associated drug responses.
• To provide an integrated resource for exploring somatic mutations, network rewiring, and drug response data for 547 kinases.
• To uniquely annotate kinase mutations in key structural regions (gatekeeper, A-loop, G-loop, αC-helix) linked to drug resistance.

Main Methods:

• Curated and integrated data from diverse sources, including 679,374 somatic mutations, 251,222 network-rewiring events, and 390,460 drug response records.
• Developed unique annotation schemes for mutations within critical kinase protein substructures.
• Annotated functional mutations, including four types of phosphorylation signal changes (gain, loss, up-regulation, down-regulation).

Main Results:

• KinaseMD integrates extensive data on kinase mutations, network rewiring, and drug response for 547 kinases.
• The database provides unique annotations of mutations in key structural domains associated with kinase inhibitor resistance.
• Functional mutations and phosphorylation signal alterations are also annotated, offering insights into kinase regulatory networks.

Conclusions:

• KinaseMD serves as a centralized, comprehensive resource for kinase mutations and drug response data.
• The database offers unique annotations, particularly regarding drug resistance mechanisms linked to specific structural mutations.
• KinaseMD facilitates research into kinase signaling, disease mechanisms, and the development of targeted therapies.