The Hallmarks of Cancer Flashcards
What are the hallmarks of cancer?
Self-suffiency in growth signals Insensitivity to antigrowth signals Tissue invasion and metastasis Limitless replication potential Sustained angiogenesis Evading apoptosis
What does the term ‘self-sufficiency in growth signals’ mean?
Cells do things which they aren’t signalled to do
Cell Signalling to do not respond to the negative signals
Why does ‘sustained angiogenesis’ effect tumour growth?
Gain new blood vessels for oxygen and nutrients which promotes growth
What are the 3 types of self sufficiency in growth factor Signalling by cancer cells
1) production of growth factors by cancer cells themselves
2) amplification or transcription up regulation of genes encoding growth factor receptors
3) mutation of genes encoding receptors and downstream components of Signalling machinerary
What is the mode of action by typical growth factors?
The growth factor binds to a tyrosine kinase receptor
The tyrosine kinase domain phosphorylase a protein and a signalling cascade occurs - eventually the transcription factor is phosphorylase and enters the nucleus = activation of genes which upregulate growth
What receptors tyrosine kinase pathway induces cancer?
The Ras-ERK pathway
Ras.GTP conformation at all time, therefore, upregulation of the downstream proteins which induce cell growth
Where is MEK phosphorylated to be activated?
2 serine residues
Where is ERK phosphorylated to be activated?
A threonine and a tyrosine residue
What effect does phosphorylation cause?
Change the protein:protein interactions
Conformational change in the protein itself
How are they able to mimic the effects of serine phosphorylation?
Use glutamic acid or aspartic acid since the negative charge of these mimic the negative charge of the phosphorylated serine
What is a common mutation in malignant melanomas?
Braf
What does RAF usually work as?
A dimerise
What does RAF become in cancer?
V600E
Name an inhibitor of Braf
PLX4720
Why is PLX4720 binding so selective for BrafV600E?
Binding site overlaps the ATP binding site
PLX4720 binds preferentially to the active conformation
What is the name of the PLX4720 drug?
Vemurafenib
How do tumours become resistant to vemurafenib?
NRAS mutation
Splice variant
CRAF overexpression
What do all of the vemurafenib resistant tumours do?
Find another way of activating the ERK pathway
What two types of drugs are thought to be quite effective together?
Braf and MEK inhibitors
Why can’t MEK inhibitors be used alone?
There is very high levels of MEK due to Braf so the drug wouldn’t be able to tackle them all
Large doses of MEK inhibitor are toxic
How may resistance to Braf inhibitor be overcome?
Use it intermittently
How is intemittent drug use thought to be effective?
1) given in small doses on and off and it does not form resistance
2) bounce back in ERK in a very high response which can also damage the cancer cell
