TY - JOUR
T1 - Therapeutic potential of MEK inhibition in acute myelogenous leukemia
T2 - Rationale for "vertical" and "lateral" combination strategies
AU - Ricciardi, Maria Rosaria
AU - Scerpa, Maria Cristina
AU - Bergamo, Paola
AU - Ciuffreda, Ludovica
AU - Petrucci, Maria Teresa
AU - Chiaretti, Sabina
AU - Tavolaro, Simona
AU - Mascolo, Maria Grazia
AU - Abrams, Stephen L.
AU - Steelman, Linda S.
AU - Tsao, Twee
AU - Marchetti, Antonio
AU - Konopleva, Marina
AU - Del Bufalo, Donatella
AU - Cognetti, Francesco
AU - Foà, Robin
AU - Andreeff, Michael
AU - McCubrey, James A.
AU - Tafuri, Agostino
AU - Milella, Michele
N1 - Funding Information:
Acknowledgments The authors wish to thank Dr. Lara Felicioni (Clinical Research Center, Center of Excellence on Aging, University-Foundation, Chieti, Italy) for her contribution to the characterization of the mutational status of the cell lines employed. This work was supported in part by grants from the Italian Association for Cancer Research (AIRC, to M.M. and D.D.B.), the Italian Ministry of Health (to M.M.), and the Cariplo Foundation (to M.M.). L.C. is a fellow of the Italian Foundation for Cancer Research (FIRC). A.T. and M.M. equally contributed to this manuscript.
PY - 2012/10
Y1 - 2012/10
N2 - In hematological malignancies, constitutive activation of the RAF/MEK/ERK pathway is frequently observed, conveys a poor prognosis, and constitutes a promising target for therapeutic intervention. Here, we investigated the molecular and functional effects of pharmacologicalMEK inhibition in cell line models of acute myeloid leukemia (AML) and freshly isolated primary AML samples. The small-molecule, ATP-non-competitive, MEK inhibitor PD0325901 markedly inhibited ERK phosphorylation and growth of several AML cell lines and approximately 70 % of primary AML samples. Growth inhibition was due to G1-phase arrest and induction of apoptosis. Transformation by constitutively active upstream pathway elements (HRAS, RAF-1, and MEK) rendered FDC-P1 cells exquisitely prone to PD0325901-induced apoptosis. Gene and protein expression profiling revealed a selective effect of PD0325901 on ERK phosphorylation and compensatory upregulation of the RAF/MEK and AKT/p70S6K kinase modules, potentially mediating resistance to drug-induced growth inhibition. Consequently, in appropriate cellular contexts, both "vertical" (i.e., inhibition of RAF and MEK along the MAPK pathway) and "lateral" (i.e., simultaneous inhibition of the MEK/ERK and mTOR pathways) combination strategies may result in synergistic anti-leukemic effects. Overall, MEK inhibition exerts potent growth inhibitory and proapoptotic activity in preclinical models of AML, particularly in combination with other pathway inhibitors. Deeper understanding of the molecular mechanisms of action of MEK inhibitors will likely translate into more effective targeted strategies for the treatment of AML.
AB - In hematological malignancies, constitutive activation of the RAF/MEK/ERK pathway is frequently observed, conveys a poor prognosis, and constitutes a promising target for therapeutic intervention. Here, we investigated the molecular and functional effects of pharmacologicalMEK inhibition in cell line models of acute myeloid leukemia (AML) and freshly isolated primary AML samples. The small-molecule, ATP-non-competitive, MEK inhibitor PD0325901 markedly inhibited ERK phosphorylation and growth of several AML cell lines and approximately 70 % of primary AML samples. Growth inhibition was due to G1-phase arrest and induction of apoptosis. Transformation by constitutively active upstream pathway elements (HRAS, RAF-1, and MEK) rendered FDC-P1 cells exquisitely prone to PD0325901-induced apoptosis. Gene and protein expression profiling revealed a selective effect of PD0325901 on ERK phosphorylation and compensatory upregulation of the RAF/MEK and AKT/p70S6K kinase modules, potentially mediating resistance to drug-induced growth inhibition. Consequently, in appropriate cellular contexts, both "vertical" (i.e., inhibition of RAF and MEK along the MAPK pathway) and "lateral" (i.e., simultaneous inhibition of the MEK/ERK and mTOR pathways) combination strategies may result in synergistic anti-leukemic effects. Overall, MEK inhibition exerts potent growth inhibitory and proapoptotic activity in preclinical models of AML, particularly in combination with other pathway inhibitors. Deeper understanding of the molecular mechanisms of action of MEK inhibitors will likely translate into more effective targeted strategies for the treatment of AML.
KW - Combinations
KW - Hematological malignancies
KW - MAPK
KW - Resistance
KW - Sensitivity
KW - Synergism
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U2 - 10.1007/s00109-012-0886-z
DO - 10.1007/s00109-012-0886-z
M3 - Article
C2 - 22399013
AN - SCOPUS:84867328500
SN - 0946-2716
VL - 90
SP - 1133
EP - 1144
JO - Journal of Molecular Medicine
JF - Journal of Molecular Medicine
IS - 10
ER -