Vertical inhibition of the mTORC1/mTORC2/PI3K pathway shows synergistic effects against melanoma in vitro and in vivo.
The phosphatidyl inositol 3-kinase/mammalian target of rapamycin (PI3K/mTOR) pathway has been shown to be involved in the development of melanoma. PI-103 is a kinase inhibitor blocking PI3K class IA and mTOR complex 1 and 2. Here, we studied the effect of targeting the PI3K/mTORC1/mTORC2 pathway by PI-103 and rapamycin in melanoma cells and in a melanoma mouse model. Dual targeting of PI3K and mTOR by PI-103 induced apoptosis and cell-cycle arrest, and inhibited viability of melanoma cells in vitro. Combined treatment with PI-103 and the prototypic mTORC1 inhibitor rapamycin led to the synergistic suppression of AKT and ribosomal S6 protein phosphorylation and to the induction of apoptosis. In vivo, PI-103 and rapamycin displayed only modest single-agent activity, but the combination significantly reduced the tumor growth compared with both single agents. These data show that blocking the PI3K/mTORC1/mTORC2 pathway using the combination of two distinct small-molecule inhibitors ("vertical inhibition") leads to superior efficacy against malignant melanoma in vitro and in vivo.
Department of Clinical Pharmacology, Section of Experimental Oncology/Molecular Pharmacology, Medical University of Vienna, Vienna, Austria.
Johannes
J
Werzowa
Stefan
S
Koehrer
Sabine
S
Strommer
Daniel
D
Cejka
Thorsten
T
Fuereder
Eva
E
Zebedin
Volker
V
Wacheck
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005663:Furans / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D000076222:Mechanistic Target of Rapamycin Complex 1; D008545:Melanoma / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D051379:Mice; D008819:Mice, Nude; D046912:Multiprotein Complexes; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011506:Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D020123:Sirolimus / Q000494:pharmacology; D012878:Skin Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D058570:TOR Serine-Threonine Kinases; D015534:Trans-Activators / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014157:Transcription Factors; D014183:Transplantation, Heterologous
D000903:Antibiotics, Antineoplastic; D004791:Enzyme Inhibitors; D005663:Furans; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011506:Proteins; D011725:Pyridines; D011743:Pyrimidines; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; D015534:Trans-Activators; D014157:Transcription Factors; C504923:Crtc2 protein, mouse; C522973:PI103