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

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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 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.

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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.

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Authors and Affiliations

  1. Division of Hematology, Department of Cellular Biotechnologies and Hematology, Sapienza University of Rome, Via Benevento 6, 00161, Rome, Italy

    Maria Rosaria Ricciardi, Maria Cristina Scerpa, Maria Teresa Petrucci, Sabina Chiaretti, Simona Tavolaro, Maria Grazia Mascolo, Robin Foà & Agostino Tafuri

  2. Division of Medical Oncology A, Regina Elena National Cancer Institute, Via Elio Chianesi 53, 00144, Rome, Italy

    Paola Bergamo, Ludovica Ciuffreda, Francesco Cognetti & Michele Milella

  3. Department of Microbiology and Immunology, Brody School of Medicine, East Carolina University, 600 Moye Blvd, 27834, Greenville, NC, USA

    Stephen L. Abrams, Linda S. Steelman & James A. McCubrey

  4. Section of Molecular Hematology and Therapy, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, 77030, Houston, TX, USA

    Twee Tsao, Marina Konopleva & Michael Andreeff

  5. Clinical Research Center, Center of Excellence on Aging, University-Foundation, Via dei Vestini 31, 66100, Chieti, Italy

    Antonio Marchetti

  6. Laboratory of Experimental Preclinical Chemotherapy, Regina Elena National Cancer Institute, Via delle Messi D’Oro 156, 00158, Rome, Italy

    Donatella Del Bufalo

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  1. Maria Rosaria Ricciardi
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  2. Maria Cristina Scerpa
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  8. Maria Grazia Mascolo
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  9. Stephen L. Abrams
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  14. Donatella Del Bufalo
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Correspondence to Michele Milella.

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Ricciardi, M.R., Scerpa, M.C., Bergamo, P. et al. Therapeutic potential of MEK inhibition in acute myelogenous leukemia: rationale for “vertical” and “lateral” combination strategies. J Mol Med 90, 1133–1144 (2012). https://doi.org/10.1007/s00109-012-0886-z

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  • DOI: https://doi.org/10.1007/s00109-012-0886-z

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