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

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

Research output: Contribution to journalArticlepeer-review

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 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.

Original languageEnglish
Pages (from-to)1133-1144
Number of pages12
JournalJournal of Molecular Medicine
Volume90
Issue number10
DOIs
Publication statusPublished - Oct 2012

Keywords

  • Combinations
  • Hematological malignancies
  • MAPK
  • Resistance
  • Sensitivity
  • Synergism

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery
  • Genetics(clinical)

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