A novel dual PI3Kalpha/mTOR inhibitor PI-103 with high antitumor activity in non-small cell lung cancer cells

Int J Mol Med. 2009 Jul;24(1):97-101. doi: 10.3892/ijmm_00000212.


PI-103, the first synthetic multitargeted compound which simultaneously inhibits PI3Kalpha and mammalian target of rapamycin (mTOR) shows high antitumor activity in glioma xenografts. In the present study, clear antitumor activity was observed with PI-103 treatment in two gefitinib-resistant non-small cell lung cancer (NSCLC) cell lines, A549 and H460, by simultaneously inhibiting p70s6k phosporylation and Akt phosphorylation in response to mTOR inhibition. In addition, H460 cells with activating mutations of PIK3CA were more sensitive to PI-103 than A549 cells with wild-type PIK3CA. PI-103 was found to inhibit growth by causing G0-G1 arrest in A549 and H460 cells. Western blotting showed that PI-103 induced down-regulation of cyclin D1 and E1 and simultaneously up-regulated p21 and p27, associated with arrest in the G0-G1 phase of the cell cycle. Furthermore, p53, the tumor suppressor which transcriptionally regulates p21, was also upregulated with PI-103 treatment. Collectively, our results suggest that multitargeted intervention is the most effective tumor therapy, and the cooperative blockade of PI3Kalpha and mTOR with PI-103 shows promise for treating gefitinib-resistant NSCLC.

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Carcinoma, Non-Small-Cell Lung
  • Cell Cycle / drug effects
  • Cell Cycle Proteins / metabolism
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Class I Phosphatidylinositol 3-Kinases
  • Drug Resistance, Neoplasm
  • Furans / pharmacology*
  • Gefitinib
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Lung Neoplasms
  • Mutation
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoinositide-3 Kinase Inhibitors*
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Kinases / metabolism*
  • Pyridines / pharmacology*
  • Pyrimidines / pharmacology*
  • Quinazolines / pharmacology
  • TOR Serine-Threonine Kinases
  • Tumor Suppressor Proteins / metabolism


  • Antineoplastic Agents
  • Cell Cycle Proteins
  • Furans
  • PI103
  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Kinase Inhibitors
  • Pyridines
  • Pyrimidines
  • Quinazolines
  • Tumor Suppressor Proteins
  • Protein Kinases
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • Class I Phosphatidylinositol 3-Kinases
  • PIK3CA protein, human
  • Gefitinib