The mitogen-activated protein kinase (MAPK) cascade controls phosphatase and tensin homolog (PTEN) expression through multiple mechanisms.
The mitogen-activated protein kinase (MAPK) and PI3K pathways are regulated by extensive crosstalk, occurring at different levels. In tumors, transactivation of the alternate pathway is a frequent "escape" mechanism, suggesting that combined inhibition of both pathways may achieve synergistic antitumor activity. Here we show that, in the M14 melanoma model, simultaneous inhibition of both MEK and mammalian target of rapamycin (mTOR) achieves synergistic effects at suboptimal concentrations, but becomes frankly antagonistic in the presence of relatively high concentrations of MEK inhibitors. This observation led to the identification of a novel crosstalk mechanism, by which either pharmacologic or genetic inhibition of constitutive MEK signaling restores phosphatase and tensin homolog (PTEN) expression, both in vitro and in vivo, and inhibits downstream signaling through AKT and mTOR, thus bypassing the need for double pathway blockade. This appears to be a general regulatory mechanism and is mediated by multiple mechanisms, such as MAPK-dependent c-Jun and miR-25 regulation. Finally, PTEN upregulation appears to be a major effector of MEK inhibitors' antitumor activity, as cancer cells in which PTEN is inactivated are consistently more resistant to the growth inhibitory and anti-angiogenic effects of MEK blockade.
Division of Medical Oncology A, Laboratory of Experimental Preclinical Chemotherapy and Translational Oncogenomics, Regina Elena National Cancer Institute, Chianesi, n. 53, 00144, Rome, Italy.
Ludovica
L
Ciuffreda
Cristina
C
Di Sanza
Ursula
U
Cesta Incani
Adriana
A
Eramo
Marianna
M
Desideri
Francesca
F
Biagioni
Daniela
D
Passeri
Italia
I
Falcone
Giovanni
G
Sette
Paola
P
Bergamo
Andrea
A
Anichini
Kanaga
K
Sabapathy
James A
JA
McCubrey
Maria Rosaria
MR
Ricciardi
Agostino
A
Tafuri
Giovanni
G
Blandino
Augusto
A
Orlandi
Ruggero
R
De Maria
Francesco
F
Cognetti
Donatella
D
Del Bufalo
Michele
M
Milella
D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D004159:Diphenylamine / Q000031:analogs & derivatives / Q000494:pharmacology; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D008545:Melanoma / Q000201:enzymology; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D015398:Signal Transduction
D001549:Benzamides; D004159:Diphenylamine; D004791:Enzyme Inhibitors; D020928:Mitogen-Activated Protein Kinases; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; C506614:mirdametinib