Insights into normal cell biology Targets for diagnosis and follow-up
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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
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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
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Signal transduction modules
Molecular links between changes in cell environment and cellular responses
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Signalling pathways control cell functions
Replicate
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
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(Hanahan & Weinberg (2000) Cell 100, 57)
The hallmarks of cancer
Many of these features may result from abnormalities in signalling components
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Ligand binding dimerizes receptor tyrosine kinases resulting in their activation
No ligand
Monomeric receptor
Ligand present
Dimeric receptor
P
PP
P
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A number of signalling modules link growth factor receptor binding to changes in cell function
P
PP
P
Activation of gene transcription
Ras PI3-kinase
STATMAPK PKB
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Ras.GDP
Ras.GTPON
OFF
GTPase activating proteine.g. NF-1
Proliferation Survival Movement
Exchange factore.g. SOS
The Ras protein acts as a molecular switch in response to changes in the external environment of the cell
Growth factor
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Recruitment of a Grb2-SOS complex to an activated receptor tyrosine kinase mediates
Ras activation
P
PP
P
SH3 SH2
GRB2SO
S
SH3 SH2
GRB2SO
SRAS
GDPGTP
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Examples of signalling pathway abnormalities in haematological
malignancy
Aberrant tyrosine kinase Bcr-Abl CMLactivity
Increased Ras activity point mutation AMLloss of NF1
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The constitutive activity of the Bcr-Abl tyrosine kinase bypasses the requirement for growth factors
Bcr-Abl
Activation of gene transcriptionIncreased proliferation/survival
RasPI3-kinase
STATMAPK PKB
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Examples of signalling pathway abnormalities in haematological malignancy
Aberrant tyrosine kinase Bcr-Abl CMLactivity
Increased Ras activity point mutation AMLloss of NF1
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AML AML
Normal
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Ras proteins are frequently activated by point mutation in human cancers
Ras.GDP
MUTANTRas.GTP
ON
OFF
NF-1
Proliferation Survival Invasion
Exchange factore.g. SOS
Carcinoma•pancreas•colon•thyroid
•AML•Myeloma
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Loss of the NF-1 protein results in excessive Ras activation
Ras.GDP
Ras.GTPON
OFF
Proliferation Survival Invasion
Neurofibromatosis•Myeloid leukaemias
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Molecular targets in leukaemia therapy
Signal transduction pathwaysDysregulated kinases eg Bcr-AblMutant Ras proteins
Apoptosis pathwaysBcl-2, NF-kappaB, p53
Differentiation pathwaysRetinoic acid receptorHistone deacetylases
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Imatinib mesylate inhibits the activity of Bcr-Abl by competing with ATP and is effective in the
treatment of CML
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Addition of a farnesyl (C15) moiety is required for Ras proteins to be active
Ras
inactive
-CAAX
Ras -C-OMe
F
active
Cytoplasm
Plasma membrane
Farnesyltransferase
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Targeting Ras proteins by inhibiting membrane localisation
Ras
inactive
-CAAXCytoplasm
Plasma membrane
Farnesyltransferase
FT Inhibitors
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The transcription factor NF-B induces transcription of pro-survival genes and is constitutively activated
in a variety of tumours
IkBNF-kB
IKK1 IKK2NEMO
NF-kB
Increased transcriptioneg Bcl-2
NIK
IkB Degradation by proteasome
P
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Inhibitors of proteasomal activity prevent NF-kB activation by blocking IkB degradation
IkBNF-kB
IKK1 IKK2NEMO
NIK
IkB
P
Proteasome inhibitorEg PS-341
Reduced transcriptionIKK inhibitors
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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