CE-L2 Oncogenes Flashcards
What is an oncogene?
A mutated proto-oncogene. The function of proto-oncogenes is to control cell growth, and so a mutation leads to loss of this control.
What are the three ways in which proto-oncogenes can be converted to oncogenes?
- Point mutation leading to increased/constitutive activation. No longer requires ligand.
- Gene amplification due to template slippage, leading to more oncogene.
- Chromosome translocation - gene moves from an area of low transcription to high trasncription e.g. Bcl-abl.
What is meant by the fact that oncogenes act in a dominant manner?
Only one mutated allelle is required for the gain of function.
What does v-scr lead to uncontrolled cell growth?
The Scr tyrosine kinase differs from normal scr in the the C-terminus with the tyrosine residue is truncated. This leads to the inability to enter the inactivate state- as it cannot be phosphorylated and bind to its SH2 domain.
What is HPV and how does it cause cancer?
HPV is an oncogenic DNA virus, it integrates viral DNA into host genome and permenantle transforms host cells.
HPV16 and 18 are known to cause 70% of cervical cancer cases.
The proteins that the virus produces do not cause cancer by mutations but instead causes it due to actions on key protiens.
What proteins does the HPV produce and how does this cause cancer?
Proteins produced by the virus are E5, 56 and E7 viral proteins.
E5 subunit causes constitutive activation of PDGFR - drives cell growth.
E6 and E7 inhibit pRB and p53 (tumour suppressor proteins) increasing growth and survival.
What are epidermal growth factors?
Proto-oncogenes important in cell proliferation.
Outline how EPGF are activated and the effects of activation.
EGF ligand binds to extracellular domain of the receptor. This causes a confirmational change and activation of the kinase domain – kinase domains dimerise and transactivate each other and autophosprhylate. This leads to activation of downstream signalling pathways:
Ras/MAPK pathway leads to proliferation
PI3K-PKB leads to cell survial.
There are two main types of EGFR receptor changes that can occur in breast cancer - discuss these and how they can be treated.
- Oncogenic mutation
- point mutation in the transmembrane region of the receptor.
- Valine (hydrophobic and so happily sits in the lipid membrane) is mutated to glutamine (charged and so is energetically unfavourable in the lipid environment)
- two chains naturally come together to minimise this disruption
- this oncoprotein is referred to as the Neu oncoprotein.
- iressa and tarceva - Amplification of WT EGF receptor
- get 100x more HER2 receptor
- leads to increased sensitivty to low levels of growth factor
- herceptin.
How does Iressa work?
Used in patients with constitutively active EGFR
Small molecule inhibitor that blocks the ATP binding site (kinase domain) and so prevents phosphorylation of downstream substrates.
Iressa only binds to a small proportion of the population with a hypermutation (10%)
Tarceva was then designed to overcome this.
How does Herceptin work?
Humanised monoclonal antibody binds to overexpressed HER2 receptor. Stops ligand binding and the receptor being activted. This will only work if we have the normal receptor, no point blocking ligand binding if the kinase is already constitutively active.
Herceptin appears to have multiple MOA that are less obviously defined, inc. downregulation of receptors, decreased Src activation and increased PTEN activation.
How can we detect HER2 postitive status?
IHC or FISH (more accurate) are commonly used.
What is herceptin used to treat?
HER+ breast cancer - both early stage and final stage patients.
How is herceptin used in the clinic? (i.e. therapeutic regimen)
Usually given in combination with doxorubicin and cyclophsophamide/paciltaxel.
Who is Herceptin not suitable for?
CI in patients with heart disease and can cause cardiotoxicity - HER2 is expressed on the heart
