AlloDriver: a method for the identification and analysis of cancer driver targets

Nucleic Acids Res. 2019 Jul 2;47(W1):W315-W321. doi: 10.1093/nar/gkz350.

Abstract

Identifying the variants that alter protein function is a promising strategy for deciphering the biological consequences of somatic mutations during tumorigenesis, which could provide novel targets for the development of cancer therapies. Here, based on our previously developed method, we present a strategy called AlloDriver that identifies cancer driver genes/proteins as possible targets from mutations. AlloDriver utilizes structural and dynamic features to prioritize potentially functional genes/proteins in individual cancers via mapping mutations generated from clinical cancer samples to allosteric/orthosteric sites derived from three-dimensional protein structures. This strategy exhibits desirable performance in the reemergence of known cancer driver mutations and genes/proteins from clinical samples. Significantly, the practicability of AlloDriver to discover novel cancer driver proteins in head and neck squamous cell carcinoma (HNSC) was tested in a real case of human protein tyrosine phosphatase, receptor type K (PTPRK) through a L1143F driver mutation located at the allosteric site of PTPRK, which was experimentally validated by cell proliferation assay. AlloDriver is expected to help to uncover innovative molecular mechanisms of tumorigenesis by perturbing proteins and to discover novel targets based on cancer driver mutations. The AlloDriver is freely available to all users at http://mdl.shsmu.edu.cn/ALD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Algorithms*
  • Allosteric Regulation
  • Allosteric Site
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / therapeutic use
  • Carcinogenesis / drug effects
  • Carcinogenesis / genetics
  • Carcinogenesis / metabolism
  • Carcinogenesis / pathology
  • Carcinoma, Squamous Cell / chemistry*
  • Carcinoma, Squamous Cell / drug therapy
  • Carcinoma, Squamous Cell / genetics
  • Carcinoma, Squamous Cell / pathology
  • Cell Line, Tumor
  • Cell Proliferation
  • Drug Discovery
  • Head and Neck Neoplasms / chemistry*
  • Head and Neck Neoplasms / drug therapy
  • Head and Neck Neoplasms / genetics
  • Head and Neck Neoplasms / pathology
  • Humans
  • Internet
  • Molecular Targeted Therapy
  • Mutation
  • Neoplasm Proteins / antagonists & inhibitors
  • Neoplasm Proteins / chemistry*
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism
  • Protein Binding
  • Protein Conformation, alpha-Helical
  • Protein Conformation, beta-Strand
  • Protein Interaction Domains and Motifs
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11 / antagonists & inhibitors
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11 / chemistry
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11 / genetics
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11 / metabolism
  • Receptor-Like Protein Tyrosine Phosphatases, Class 2 / antagonists & inhibitors
  • Receptor-Like Protein Tyrosine Phosphatases, Class 2 / chemistry*
  • Receptor-Like Protein Tyrosine Phosphatases, Class 2 / genetics
  • Receptor-Like Protein Tyrosine Phosphatases, Class 2 / metabolism
  • Software*

Substances

  • Antineoplastic Agents
  • Neoplasm Proteins
  • PTPN11 protein, human
  • PTPRK protein, human
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11
  • Receptor-Like Protein Tyrosine Phosphatases, Class 2