Therapeutic potential of MEK inhibition in acute myelogenous leukemia: rationale for "vertical" and "lateral" combination strategies.

Abstract

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 pharmacological MEK 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 G(1)-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/p70( S6K ) 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.

• Authors: Maria Rosaria Ricciardi, Maria Cristina Scerpa, Paola Bergamo, Ludovica Ciuffreda, Maria Teresa Petrucci, Sabina Chiaretti, Simona Tavolaro, Maria Grazia Mascolo, Stephen L Abrams, Linda S Steelman, Twee Tsao, Antonio Marchetti, Marina Konopleva, Donatella Del Bufalo, Francesco Cognetti, Robin Foà, Michael Andreeff, James A McCubrey, Agostino Tafuri, Michele Milella
• Journal: Journal of molecular medicine (Berlin, Germany) (J Mol Med (Berl)) Vol. 90 Issue 10 Pg. 1133-44 (Oct 2012) ISSN: 1432-1440 [Electronic] Germany
• PMID: 22399013 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Benzamides
• Benzenesulfonates
• Intracellular Signaling Peptides and Proteins
• Phenylurea Compounds
• Pyridines
• Niacinamide
• mirdametinib
• Diphenylamine
• Sorafenib
• Proto-Oncogene Proteins c-akt
• Proto-Oncogene Proteins c-raf
• Extracellular Signal-Regulated MAP Kinases
• MAP Kinase Kinase 1
• MAP2K1 protein, human

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Benzamides (pharmacology)
• Benzenesulfonates (pharmacology)
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Diphenylamine (analogs & derivatives, pharmacology)
• Drug Resistance, Neoplasm
• Drug Synergism
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Humans
• Inhibitory Concentration 50
• Intracellular Signaling Peptides and Proteins (metabolism)
• Leukemia, Myeloid, Acute (drug therapy)
• MAP Kinase Kinase 1 (antagonists & inhibitors)
• Niacinamide (analogs & derivatives)
• Oligonucleotide Array Sequence Analysis
• Phenylurea Compounds
• Phosphorylation
• Proto-Oncogene Proteins c-akt (metabolism)
• Proto-Oncogene Proteins c-raf (antagonists & inhibitors, metabolism)
• Pyridines (pharmacology)
• Signal Transduction
• Sorafenib
• Transcriptome (drug effects)
• Tumor Cells, Cultured (drug effects)