The mitogen-activated protein kinase (MAPK) pathway regulates growth and survival of many cell types, and its constitutive activation has been implicated in the pathogenesis of a variety of malignancies. In this study we demonstrate that small-molecule MEK inhibitors (PD98059 and PD184352) profoundly impair cell growth and survival of acute myeloid leukemia (AML) cell lines and primary samples with constitutive MAPK activation. These agents abrogate the clonogenicity of leukemic cells but have minimal effects on normal hematopoietic progenitors. MEK blockade also results in sensitization to spontaneous and drug-induced apoptosis. At a molecular level, these effects correlate with modulation of the expression of cyclin-dependent kinase inhibitors (p27Kip1 and p21Waf1/CIP1) and antiapoptotic proteins of the inhibitor of apoptosis proteins (IAP) and Bcl-2 families. Interruption of constitutive MEK/MAPK signaling therefore represents a promising therapeutic strategy in AML.
Michele Milella, Steven M. Kornblau, Zeev Estrov, Bing Z. Carter, Hélène Lapillonne, David Harris, Marina Konopleva, Shourong Zhao, Elihu Estey, Michael Andreeff
Title and authors | Publication | Year |
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The MEK Inhibitor Trametinib Separates Murine Graft-versus-Host Disease from Graft-versus-Tumor Effects
Hidekazu Itamura, Takero Shindo, Isao Tawara, Yasushi Kubota, Ryusho Kariya, Seiji Okada, Krishna V. Komanduri, Shinya Kimura |
JCI Insight | 2016 |
CD98-Mediated Adhesive Signaling Enables the Establishment and Propagation of Acute Myelogenous Leukemia
J Bajaj, T Konuma, NK Lytle, HY Kwon, JN Ablack, JM Cantor, D Rizzieri, C Chuah, VG Oehler, EH Broome, ED Ball, EH van der Horst, MH Ginsberg, T Reya |
Cancer Cell | 2016 |
Activity of the oral mitogen-activated protein kinase kinase inhibitor trametinib in RAS -mutant relapsed or refractory myeloid malignancies: Trametinib in RAS -Mutant Malignancies
G Borthakur, L Popplewell, M Boyiadzis, J Foran, U Platzbecker, N Vey, RB Walter, R Olin, A Raza, A Giagounidis, A Al-Kali, E Jabbour, T Kadia, G Garcia-Manero, JW Bauman, Y Wu, Y Liu, D Schramek, DS Cox, P Wissel, H Kantarjian |
Cancer | 2016 |
Tetraspanin CD82 Regulates the Spatiotemporal Dynamics of PKCα in Acute Myeloid Leukemia
CM Termini, KA Lidke, JM Gillette |
Scientific Reports | 2016 |
The HER2 inhibitor TAK165 Sensitizes Human Acute Myeloid Leukemia Cells to Retinoic Acid-Induced Myeloid Differentiation by activating MEK/ERK mediated RARα/STAT1 axis
X Shao, Y Liu, Y Li, M Xian, Q Zhou, B Yang, M Ying, Q He |
Scientific Reports | 2016 |
Tobacco Smoke and Ras Mutations Among Latino and Non-Latino Children with Acute Lymphoblastic Leukemia
M Kaur, AJ de Smith, S Selvin, L Zhang, M Cunningham, MW Kang, HM Hansen, RM Cooper, R McKean-Cowdin, JL Wiemels, C Metayer |
Archives of Medical Research | 2016 |
Analyzing tumor heterogeneity and driver genes in single myeloid leukemia cells with SBCapSeq
KM Mann, JY Newberg, MA Black, DJ Jones, F Amaya-Manzanares, L Guzman-Rojas, T Kodama, JM Ward, AG Rust, L van der Weyden, CC Yew, JL Waters, ML Leung, K Rogers, SM Rogers, LA McNoe, L Selvanesan, N Navin, NA Jenkins, NG Copeland, MB Mann |
Nature Biotechnology | 2016 |
Down-Regulation of Ribosomal S6 kinase RPS6KA6 in Acute Myeloid Leukemia Patients.
Rafiee M, Keramati MR, Ayatollahi H, Sadeghian MH, Barzegar M, Asgharzadeh A, Alinejad M |
2016 |