Pre-clinical use of isogenic cell lines and tumours in vitro and in vivo for predictive biomarker discovery; impact of KRAS and PI3KCA mutation status on MEK inhibitor activity is model dependent

Eur J Cancer. 2016 Mar:56:69-76. doi: 10.1016/j.ejca.2015.12.012. Epub 2016 Jan 25.

Abstract

Studies to identify predictive biomarkers can be carried out in isogenic cancer cell lines, which enable interrogation of the effect of a specific mutation. We assessed the effects of four drugs, the PI3K-mammalian target of rapamycin inhibitor dactolisib, the PI3K inhibitor pictrelisib, and the MEK (MAPK/ERK Kinase) inhibitors PD 0325901 and selumetinib, in isogenic DLD1 parental, KRAS(+/-), KRAS(G13D/-), PIK3CA(+/-) and PIK3CA(E545K/-) colorectal carcinoma cell lines. Importantly, we found substantial differences in the growth of these cells and in their drug sensitivity depending on whether they were studied under 2D (standard tissue culture on plastic) or 3D (in vitro soft agar and in vivo xenograft) conditions. DLD1 KRAS(+/-) and DLD1 PIK3CA(+/-) cells were more sensitive to MEK inhibitors than parental, DLD1 KRAS(G13D/-) and DLD1 PIK3CA(E545K/-) cells under 2D conditions, whereas DLD1 KRAS(G13D/-) and DLD1 PIK3CA(E545K/-) xenografts were sensitive to 10 mg/kg daily ×14 PD 0325901 in vivo (p ≤ 0.02) but tumours derived from parental DLD1 cells were not. These findings indicate that KRAS and PIK3CA mutations can influence the response of DLD1 colorectal cancer cell lines to MEK and PI3K inhibitors, but that the effect is dependent on the experimental model used to assess drug sensitivity.

Keywords: Biomarker; Combination; Isogenic; MEK; PI3K.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Biomarkers, Tumor* / antagonists & inhibitors
  • Biomarkers, Tumor* / genetics
  • Biomarkers, Tumor* / metabolism
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Class I Phosphatidylinositol 3-Kinases
  • Colorectal Neoplasms / drug therapy*
  • Colorectal Neoplasms / enzymology
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms / pathology
  • Dose-Response Relationship, Drug
  • Female
  • Humans
  • MAP Kinase Kinase Kinases / antagonists & inhibitors*
  • MAP Kinase Kinase Kinases / metabolism
  • Mice, Nude
  • Mutation*
  • Phosphatidylinositol 3-Kinases / genetics*
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoinositide-3 Kinase Inhibitors*
  • Protein Kinase Inhibitors / pharmacology*
  • Proto-Oncogene Proteins p21(ras) / genetics*
  • Signal Transduction / drug effects
  • TOR Serine-Threonine Kinases / antagonists & inhibitors
  • TOR Serine-Threonine Kinases / metabolism
  • Time Factors
  • Tumor Burden / drug effects
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • Biomarkers, Tumor
  • KRAS protein, human
  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Kinase Inhibitors
  • MTOR protein, human
  • Class I Phosphatidylinositol 3-Kinases
  • PIK3CA protein, human
  • TOR Serine-Threonine Kinases
  • MAP Kinase Kinase Kinases
  • Proto-Oncogene Proteins p21(ras)