The Raf/MEK/ERK pathway can govern drug resistance, apoptosis and sensitivity to targeted therapy.
The effects of the Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR signaling pathways on proliferation, drug resistance, prevention of apoptosis and sensitivity to signal transduction inhibitors were examined in FL/DeltaAkt-1:ER*(Myr(+)) + DeltaRaf-1:AR cells which are conditionally-transformed to grow in response to Raf and Akt activation. Drug resistant cells were isolated from FL/DeltaAkt-1:ER*(Myr(+)) + DeltaRaf-1:AR cells in the presence of doxorubicin. Activation of Raf-1, in the drug resistant FL/DeltaAkt-1:ER*(Myr(+)) + DeltaRaf-1:AR cells, increased the IC(50) for doxorubicin 80-fold, whereas activation of Akt-1, by itself, had no effect on the doxorubicin IC50. However, Akt-1 activation enhanced cell proliferation and clonogenicity in the presence of chemotherapeutic drugs. Thus the Raf/MEK/ERK pathway had profound effects on the sensitivity to chemotherapeutic drugs, and Akt-1 activation was required for the long term growth of these cells as well as resistance to chemotherapeutic drugs. The effects of doxorubicin on the induction of apoptosis in the drug resistant cells were enhanced by addition of either mTOR and MEK inhibitors. These results indicate that targeting the Raf/MEK/ERK and PI3K/Akt/mTOR pathways may be an effective approach for therapeutic intervention in drug resistant cancers that have mutations activating these cascades.
Abrams
Stephen L
SL
Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC, USA.
Steelman
Linda S
LS
Shelton
John G
JG
Wong
Ellis W T
EW
Chappell
William H
WH
Bäsecke
Jörg
J
Stivala
Franca
F
Donia
Marco
M
Nicoletti
Ferdinando
F
Libra
Massimo
M
Martelli
Alberto M
AM
McCubrey
James A
JA
D000970:Antineoplastic Agents / Q000627:therapeutic use; D017209:Apoptosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004317:Doxorubicin / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy / Q000378:metabolism; D020935:MAP Kinase Signaling System; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D048490:raf Kinases / Q000378:metabolism*
D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D004317:Doxorubicin; D051057:Proto-Oncogene Proteins c-akt; D048490:raf Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D020929:Mitogen-Activated Protein Kinase Kinases