Proteomic analysis defines kinase taxonomies specific for subtypes of breast cancer

Kyla A L Collins1, Timothy J Stuhlmiller2,3, Jon S Zawistowski2,3

  • 1Curriculum in Bioinformatics and Computational Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA.

Oncotarget
|April 13, 2018
PubMed

Insights

Multiplexed small molecule inhibitors bound to beads (MIBs) proteomically distinguished breast cancer subtypes. This method integrates understudied kinases into signaling networks, aiding subtype classification and understanding adaptive changes.

Area of Science:

  • Proteomics
  • Cancer Biology
  • Biochemistry

Background:

  • Breast cancer comprises distinct subtypes with varying clinical outcomes.
  • Kinase signaling pathways are crucial in cancer development and progression.
  • Many kinases remain understudied, limiting therapeutic strategies.

Purpose of the Study:

  • To develop a proteomics-based method for profiling functional kinases across breast cancer subtypes.
  • To integrate understudied kinases into functional signaling networks.
  • To investigate adaptive kinome reprogramming in response to targeted inhibition.

Main Methods:

  • Utilized multiplexed small molecule inhibitors covalently bound to Sepharose beads (MIBs) to capture kinases.
  • Analyzed MIB-binding profiles from luminal, HER2-enriched, and triple-negative breast cancer cell lines and tumors.
  • Employed computational analysis to define subtypes using kinase profiles.

Main Results:

  • MIB-binding profiles proteomically distinguished the four breast cancer subtypes at baseline.
  • Understudied kinases were identified and integrated into signaling subnetworks with well-characterized kinases.
  • Subtypes could be defined using profiles of fewer than 50 kinases, including understudied, metabolic, and lipid kinases.
  • MIB profiles revealed subtype-selective adaptive kinome reprogramming upon targeted kinase inhibition.

Conclusions:

  • MIBs provide a unique proteomics approach to integrate understudied kinases into functional subnetworks for breast cancer.
  • MIB-binding profiles can define subtypes and reveal dynamic kinome changes driving phenotypic state alterations.
  • This method offers a powerful tool for understanding kinase function and developing targeted therapies in diverse breast cancer subtypes.

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