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Transcript
What can we learn from the identification of
specific molecular abnormalities in malignant
disease?
•Insights into normal cell biology
•Targets for diagnosis and follow-up
•Targets for rational drug design
Conventional cytotoxic drugs mainly act
by causing DNA damage and cell death
Studying the biology of cancer cells may
provide new targets for drug development
Signal transduction modules
Molecular links between changes in cell
environment and cellular responses
Signalling pathways control cell
functions
Replicate
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Live/Die
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Signal transduction modules
Molecular links between changes in cell
environment and cellular responses
e.g.
•Erythropoietin and prevention of apoptosis in
erythroid progenitors
•G-CSF and proliferation in myeloid progenitors
The hallmarks
of cancer
Many of these
features may result
from abnormalities
in signalling
components
(Hanahan &
Weinberg (2000)
Cell 100, 57)
Ligand binding dimerizes receptor tyrosine
kinases resulting in their activation
Monomeric receptor
Dimeric receptor
P
P
No ligand
P
P
Ligand present
A number of signalling modules link growth factor
receptor binding to changes in cell function
Ras
MAPK
P
P
P
P
STAT
Activation of gene transcription
PI3-kinase
PKB
The Ras protein acts as a molecular switch in response
to changes in the external environment of the cell
Growth factor
OFF
Ras.GDP
GTPase
activating protein
e.g. NF-1
Proliferation
Exchange factor
e.g. SOS
Ras.GTP
ON
Survival
Movement
RAS
SH3
SH2
GRB2
GDP
SOS
GTP
SOS
Recruitment of a Grb2-SOS complex to an
activated receptor tyrosine kinase mediates Ras
activation
SH3
SH2
GRB2
P
P
P
P
Examples of signalling pathway
abnormalities in haematological
malignancy
Aberrant tyrosine kinase
activity
Bcr-Abl
CML
Increased Ras activity
point mutation
loss of NF1
AML
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The constitutive activity of the Bcr-Abl tyrosine
kinase bypasses the requirement for growth factors
Bcr-Abl
Ras
MAPK
PI3-kinase
STAT
PKB
Activation of gene transcription
Increased proliferation/survival
Examples of signalling pathway abnormalities
in haematological malignancy
Aberrant tyrosine kinase
activity
Bcr-Abl
CML
Increased Ras activity
point mutation
loss of NF1
AML
AML
AML
Normal
Ras proteins are frequently activated by
point mutation in human cancers
OFF
Ras.GDP
Exchange
factor
e.g. SOS
NF-1
MUTANT
Ras.GTP
ON
Proliferation
Survival
Carcinoma
•pancreas
•colon
•thyroid
•AML
•Myeloma
Invasion
Loss of the NF-1 protein results in
excessive Ras activation
OFF
Ras.GDP
Neurofibromatosis
•Myeloid leukaemias
Ras.GTP
ON
Proliferation
Survival
Invasion
Molecular targets in leukaemia
therapy
Signal transduction pathways
Dysregulated kinases eg Bcr-Abl
Mutant Ras proteins
Apoptosis pathways
Bcl-2, NF-kappaB, p53
Differentiation pathways
Retinoic acid receptor
Histone deacetylases
Imatinib mesylate inhibits the activity of Bcr-Abl
by competing with ATP and is effective in the
treatment of CML
Addition of a farnesyl (C15) moiety is
required for Ras proteins to be active
Plasma membrane
Ras
Farnesyl
transferase
Ras
active
-CAAX
Cytoplasm
inactive
F
-C-OMe
Targeting Ras proteins by inhibiting
membrane localisation
Plasma membrane
Farnesyl
transferase
Ras
FT Inhibitors
-CAAX
Cytoplasm
inactive
The transcription factor NF-kB induces transcription
of pro-survival genes and is constitutively activated
in a variety of tumours
NIK
NEMO
IKK1
IkB
IKK2
P
IkB
NF-kB
Degradation by
proteasome
NF-kB
Increased transcription
eg Bcl-2
Inhibitors of proteasomal activity prevent NF-kB
activation by blocking IkB degradation
Proteasome inhibitor
Eg PS-341
NIK
NEMO
IKK1
IkB
IKK2
P
IKK inhibitors
IkB
NF-kB
Reduced transcription
What can we learn from the identification of
specific molecular abnormalities in malignant
disease?
•Insights into normal cell biology
•Targets for diagnosis and follow-up
•Targets for rational drug design