Selective PI3K inhibition by BKM120 and BEZ235 alone or in combination with chemotherapy in wild-type and mutated human gastrointestinal cancer cell lines

Cancer Chemother Pharmacol. 2012 Jun;69(6):1601-15. doi: 10.1007/s00280-012-1869-z. Epub 2012 Apr 29.


Purpose: New targeted agents like antibodies or small molecules against tyrosine and lipid kinases clearly expand the standard therapy options in oncology. However, tumour resistance is still a challenge, often induced by mutations in growth-related signalling cascades. Twenty and ten percentage of all patients with colorectal and gastric cancers, respectively, carry phosphatidyl-3-kinase (PI3K) mutations and do not respond to receptor-blocking therapies. Recently, selective kinase inhibitors have been generated, which block the PI3K signalling pathway in tumour cells. So far, their therapeutic role for the treatment of mutated versus wild-type human gastrointestinal cancers has not been clarified in detail.

Methods: To define the inhibitory and pro-apoptotic effects of the two PI3K inhibitors BEZ235 and BKM120 in three human colon cancer (HT-29, HCT-116 and DLD-1) and three gastric cancer (NCI-n87, AGS and MKN-45), cell lines with different PIK3CA gene mutation status were used. Firstly, viability, apoptosis and caspase assays were performed during incubation with either the inhibitors alone or combined with different cytotoxic agents. Secondly, the molecular consequences for the cell cycle and signalling pathways were analysed by defining the protein levels by FACS and Western blot analysis.

Results: Both the PI3K inhibitors BEZ235 and BKM120 induced a clear concentration-dependent reduction in cell viability and an increase in apoptotic cell death, with the mutated cells being more sensitive to treatment. However, single-agent BEZ235 caused a G1 arrest in tumour cells, whilst BKM120 induced a G2 shift in a half of the gastrointestinal cancer cell lines. There was a clear downregulation in the protein levels of the PI3K-AKT pathway at the concentrations of 100 nM for both agents and for BEZ235 the additional inhibition of the mTOR pathway. Furthermore, BEZ235 caused synergistic induction of apoptosis when combined with irinotecan in colon cancer cell lines. Human gastric cancer cells were less sensitive to both BEZ235 and BKM120.

Conclusions: BEZ235 and BKM120 induced pro-apoptotic effects in all cell lines and especially with an increased response in the PI3KCA mutated cells. Our data support the clinical development of these PI3K inhibitors for patients with wild-type or mutated colon cancers.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminopyridines / administration & dosage
  • Aminopyridines / therapeutic use*
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Camptothecin / analogs & derivatives
  • Camptothecin / pharmacology
  • Caspase 3 / biosynthesis
  • Cell Cycle Checkpoints / drug effects
  • Cell Survival / drug effects
  • Dose-Response Relationship, Drug
  • Gastrointestinal Neoplasms / drug therapy*
  • Gastrointestinal Neoplasms / genetics
  • Gastrointestinal Neoplasms / pathology
  • HCT116 Cells
  • HT29 Cells
  • Humans
  • Imidazoles / administration & dosage
  • Imidazoles / therapeutic use*
  • Irinotecan
  • Morpholines / administration & dosage
  • Morpholines / therapeutic use*
  • Mutation
  • Phosphoinositide-3 Kinase Inhibitors*
  • Protein Kinase Inhibitors / therapeutic use*
  • Proto-Oncogene Proteins c-akt / antagonists & inhibitors
  • Proto-Oncogene Proteins c-akt / physiology
  • Quinolines / administration & dosage
  • Quinolines / therapeutic use*
  • Signal Transduction / physiology
  • TOR Serine-Threonine Kinases / antagonists & inhibitors
  • TOR Serine-Threonine Kinases / physiology


  • Aminopyridines
  • Imidazoles
  • Morpholines
  • NVP-BKM120
  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Kinase Inhibitors
  • Quinolines
  • Irinotecan
  • TOR Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Caspase 3
  • dactolisib
  • Camptothecin