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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 Move 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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The hallmarks of cancer
Many of these features may result from abnormalities in signalling components (Hanahan & Weinberg (2000) Cell 100, 57)
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Ligand binding dimerizes receptor tyrosine kinases resulting in their activation
Monomeric receptor Dimeric receptor P P P P No ligand Ligand present
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A number of signalling modules link growth factor receptor binding to changes in cell function
Ras PI3-kinase P P MAPK STAT PKB Activation of gene transcription
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The Ras protein acts as a molecular switch in response
to changes in the external environment of the cell Growth factor OFF Ras.GDP Exchange factor e.g. SOS GTPase activating protein e.g. NF-1 Ras.GTP ON Proliferation Survival Movement
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Recruitment of a Grb2-SOS complex to an activated receptor tyrosine kinase mediates Ras activation
SH3 SH2 GRB2 SOS P P P P GTP GDP SH3 SH2 GRB2 SOS
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Examples of signalling pathway abnormalities in haematological malignancy
Aberrant tyrosine kinase Bcr-Abl CML activity Increased Ras activity point mutation AML loss of NF1
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The constitutive activity of the Bcr-Abl tyrosine kinase bypasses the requirement for growth factors
Ras PI3-kinase MAPK STAT PKB Activation of gene transcription Increased proliferation/survival
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Examples of signalling pathway abnormalities in haematological malignancy
Aberrant tyrosine kinase Bcr-Abl CML activity Increased Ras activity point mutation AML loss of NF1
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AML AML Normal
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Ras proteins are frequently activated by point mutation in human cancers
OFF Ras.GDP Carcinoma pancreas colon thyroid AML Myeloma Exchange factor e.g. SOS NF-1 MUTANT Ras.GTP ON Proliferation Survival Invasion
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Loss of the NF-1 protein results in excessive Ras activation
OFF Ras.GDP Neurofibromatosis Myeloid leukaemias Ras.GTP ON Proliferation Survival Invasion
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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
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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
Plasma membrane Ras -C-OMe Farnesyl transferase active Ras -CAAX Cytoplasm inactive
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Targeting Ras proteins by inhibiting membrane localisation
Plasma membrane Farnesyl transferase FT Inhibitors Ras -CAAX Cytoplasm inactive
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Increased transcription
The transcription factor NF-kB induces transcription of pro-survival genes and is constitutively activated in a variety of tumours NIK IkB Degradation by proteasome NEMO IKK1 IKK2 P IkB NF-kB NF-kB Increased transcription eg Bcl-2
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Inhibitors of proteasomal activity prevent NF-kB activation by blocking IkB degradation
Proteasome inhibitor Eg PS-341 NIK IkB NEMO IKK1 IKK2 P IkB NF-kB IKK inhibitors Reduced transcription
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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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