Targeting melanoma with dual phosphoinositide 3-kinase/mammalian target of rapamycin inhibitors

Mol Cancer Res. 2009 Apr;7(4):601-13. doi: 10.1158/1541-7786.MCR-08-0366.

Abstract

Phosphoinositide 3-kinase (PI3K)/protein kinase B/Akt and Ras/mitogen-activated protein kinase pathways are often constitutively activated in melanoma and have thus been considered as promising drug targets. Exposure of melanoma cells to NVP-BAG956, NVP-BBD130, and NVP-BEZ235, a series of novel, potent, and stable dual PI3K/mammalian target of rapamycin (mTOR) inhibitors, resulted in complete G1 growth arrest, reduction of cyclin D1, and increased levels of p27(KIP1), but negligible apoptosis. In contrast, treatment of melanoma with the pan-class I PI3K inhibitor ZSTK474 or the mTORC1 inhibitor rapamycin resulted only in minor reduction of cell proliferation. In a syngeneic B16 mouse melanoma tumor model, orally administered NVP-BBD130 and NVP-BEZ235 efficiently attenuated tumor growth at primary and lymph node metastatic sites with no obvious toxicity. Metastatic melanoma in inhibitor-treated mice displayed reduced numbers of proliferating and significantly smaller tumor cells. In addition, neovascularization was blocked and tumoral necrosis increased when compared with vehicle-treated mice. In conclusion, compounds targeting PI3K and mTOR simultaneously were advantageous to attenuate melanoma growth and they develop their potential by targeting tumor growth directly, and indirectly via their interference with angiogenesis. Based on the above results, NVP-BEZ235, which has entered phase I/II clinical trials in patients with advanced solid tumors, has a potential in metastatic melanoma therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3-Phosphoinositide-Dependent Protein Kinases
  • Administration, Oral
  • Animals
  • Antibiotics, Antineoplastic / pharmacology
  • Apoptosis / physiology
  • Cell Cycle / drug effects
  • Cell Proliferation / drug effects
  • Drug Synergism
  • Female
  • Forkhead Box Protein O1
  • Forkhead Transcription Factors / metabolism
  • Humans
  • Imidazoles / pharmacology*
  • Immunoblotting
  • Immunoenzyme Techniques
  • Melanoma, Experimental / drug therapy*
  • Melanoma, Experimental / pathology
  • Mice
  • Mice, Inbred C57BL
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoinositide-3 Kinase Inhibitors*
  • Protein Kinases / metabolism*
  • Protein Transport
  • Protein-Serine-Threonine Kinases / metabolism
  • Quinolines / pharmacology*
  • Sirolimus / pharmacology*
  • TOR Serine-Threonine Kinases
  • Triazines / pharmacology*
  • Tumor Cells, Cultured

Substances

  • Antibiotics, Antineoplastic
  • Forkhead Box Protein O1
  • Forkhead Transcription Factors
  • Foxo1 protein, mouse
  • Imidazoles
  • Phosphoinositide-3 Kinase Inhibitors
  • Quinolines
  • Triazines
  • ZSTK474
  • Protein Kinases
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse
  • 3-Phosphoinositide-Dependent Protein Kinases
  • Protein-Serine-Threonine Kinases
  • dactolisib
  • Sirolimus