Molecular Profiling Establishes Genetic Features Predictive of the Efficacy of the p110β Inhibitor KIN-193

Cancer Res. 2019 Sep 1;79(17):4524-4531. doi: 10.1158/0008-5472.CAN-19-0588. Epub 2019 Jul 10.

Abstract

Aberrant activation of the PI3K pathway is a common alteration in human cancers. Therapeutic intervention targeting the PI3K pathway has achieved limited success due to the intricate balance of its different components and isoforms. Here, we systematically investigated the genomic and transcriptomic signatures associated with response to KIN-193, a compound specifically targeting the p110β isoform. By integrating genomic, transcriptomic, and drug response profiles from the Genomics of Drug Sensitivity in Cancer database, we identified mutational and transcriptomic signatures associated with KIN-193 and further created statistical models to predict the treatment effect of KIN-193 in cell lines, which may eventually be clinically valuable. These predictions were validated by analysis of the external Cancer Cell Line Encyclopedia dataset. These results may assist precise therapeutic intervention targeting the PI3K pathway. SIGNIFICANCE: These findings provide new insights into molecular signatures associated with sensitivity of the p110β inhibitor KIN-193, which may provide a useful guide for developing precise treatment methods for cancer.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • Class Ia Phosphatidylinositol 3-Kinase
  • Databases, Factual
  • Drug Resistance, Neoplasm / drug effects
  • Drug Resistance, Neoplasm / genetics*
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Machine Learning
  • Models, Statistical
  • Mutation
  • Neoplasms / drug therapy
  • Neoplasms / genetics
  • Neoplasms / pathology
  • PTEN Phosphohydrolase / genetics
  • Phosphoinositide-3 Kinase Inhibitors / pharmacology*
  • Pyrimidinones / pharmacology*
  • Reproducibility of Results
  • Treatment Outcome
  • ortho-Aminobenzoates / pharmacology*

Substances

  • 2-(1-(7-methyl-2-morpholin-4-yl-4-oxo-4H-pyrido(1,2-a)pyrimidin-9-yl)ethylamino)benzoic acid
  • Antineoplastic Agents
  • Phosphoinositide-3 Kinase Inhibitors
  • Pyrimidinones
  • ortho-Aminobenzoates
  • Class Ia Phosphatidylinositol 3-Kinase
  • PTEN Phosphohydrolase
  • PTEN protein, human