Naturally Occurring Mutations in the MPS1 Gene Predispose Cells to Kinase Inhibitor Drug Resistance

Cancer Res. 2015 Aug 15;75(16):3340-54. doi: 10.1158/0008-5472.CAN-14-3272. Epub 2015 Jul 22.

Abstract

Acquired resistance to therapy is perhaps the greatest challenge to effective clinical management of cancer. With several inhibitors of the mitotic checkpoint kinase MPS1 in preclinical development, we sought to investigate how resistance against these inhibitors may arise so that mitigation or bypass strategies could be addressed as early as possible. Toward this end, we modeled acquired resistance to the MPS1 inhibitors AZ3146, NMS-P715, and CCT251455, identifying five point mutations in the kinase domain of MPS1 that confer resistance against multiple inhibitors. Structural studies showed how the MPS1 mutants conferred resistance by causing steric hindrance to inhibitor binding. Notably, we show that these mutations occur in nontreated cancer cell lines and primary tumor specimens, and that they also preexist in normal lymphoblast and breast tissues. In a parallel piece of work, we also show that the EGFR p.T790M mutation, the most common mutation conferring resistance to the EGFR inhibitor gefitinib, also preexists in cancer cells and normal tissue. Our results therefore suggest that mutations conferring resistance to targeted therapy occur naturally in normal and malignant cells and these mutations do not arise as a result of the increased mutagenic plasticity of cancer cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aniline Compounds / chemistry
  • Aniline Compounds / metabolism
  • Aniline Compounds / pharmacology
  • Cell Cycle Proteins / chemistry
  • Cell Cycle Proteins / genetics*
  • Cell Cycle Proteins / metabolism
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cell Survival / genetics
  • Dose-Response Relationship, Drug
  • Drug Resistance, Neoplasm / genetics*
  • ErbB Receptors / antagonists & inhibitors
  • Gefitinib
  • HCT116 Cells
  • HEK293 Cells
  • Heterocyclic Compounds, 2-Ring / chemistry
  • Heterocyclic Compounds, 2-Ring / metabolism
  • Heterocyclic Compounds, 2-Ring / pharmacology
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Neoplasms / genetics
  • Neoplasms / metabolism
  • Neoplasms / pathology
  • Point Mutation*
  • Protein Binding
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / metabolism
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Serine-Threonine Kinases / chemistry
  • Protein Serine-Threonine Kinases / genetics*
  • Protein Serine-Threonine Kinases / metabolism
  • Protein Structure, Tertiary
  • Protein-Tyrosine Kinases / chemistry
  • Protein-Tyrosine Kinases / genetics*
  • Protein-Tyrosine Kinases / metabolism
  • Pyrazoles / chemistry
  • Pyrazoles / metabolism
  • Pyrazoles / pharmacology
  • Quinazolines / chemistry
  • Quinazolines / metabolism
  • Quinazolines / pharmacology

Substances

  • Aniline Compounds
  • Cell Cycle Proteins
  • Heterocyclic Compounds, 2-Ring
  • N-(2,6-diethylphenyl)-1-methyl-8-((4-((1-methylpiperidin-4-yl)carbamoyl)-2-(trifluoromethoxy)phenyl)amino)-4,5-dihydro-1H-pyrazolo(4,3-h)quinazoline-3-carboxamide
  • Protein Kinase Inhibitors
  • Pyrazoles
  • Quinazolines
  • tert-butyl 6-(2-chloro-4-(1-methyl-1H-imidazol-5-yl)phenylamino)-2-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo(3,2-c)pyridine-1-carboxylate
  • ErbB Receptors
  • Protein-Tyrosine Kinases
  • Protein Serine-Threonine Kinases
  • TTK protein, human
  • Gefitinib