Targeting melanoma with dual phosphoinositide 3-kinase/mammalian target of rapamycin inhibitors.
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.
Department of Biomedicine, University of Basel, Mattenstrasse 28, CH-4058 Basel, Switzerland.
Romina
R
Marone
Dominik
D
Erhart
Ann C
AC
Mertz
Thomas
T
Bohnacker
Christian
C
Schnell
Vladimir
V
Cmiljanovic
Frédéric
F
Stauffer
Carlos
C
Garcia-Echeverria
Bernd
B
Giese
Sauveur-Michel
SM
Maira
Matthias P
MP
Wymann
D064413:3-Phosphoinositide-Dependent Protein Kinases; D000284:Administration, Oral; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis / Q000502:physiology; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004357:Drug Synergism; D005260:Female; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D015151:Immunoblotting; D007124:Immunoenzyme Techniques; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011494:Protein Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D021381:Protein Transport; D011804:Quinolines / Q000494:pharmacology*; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases; D014227:Triazines / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D064413:3-Phosphoinositide-Dependent Protein Kinases; D000903:Antibiotics, Antineoplastic; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D007093:Imidazoles; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D011804:Quinolines; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; D014227:Triazines; C467200:Foxo1 protein, mouse; C510150:ZSTK474; C546842:MTOR protein, human; C546843:mTOR protein, mouse; C531198:dactolisib