CE L2 Proto-oncogenes Flashcards
3 e.g. of proto-oncogenes
EGFR
Ras
Src
Until ……… discovery it was thought cancer was transmitted.
virus containing oncogene v-src identified.
but normal cells contain a v-src like genes.
So cancer is caused by action of near normal genes
only human oncogenic retrovirus is
HTLV
How does v-src containing virus cause cancer
Viral gene incorporation into host DNA, when it is excised it cuts out some host DNA (Src).
In normal cells with Src the C terminal is phosphorlated so tyrosine kinast is inactive and cannot interact with substrate. When active the C terminal gets dephosphorylated.
The C terminal is now cut off therefore constituatively active (cannot be phosphorylated to deactivate)
V-src doesnt actually cause mutations by…
affects the function of key proteins
V-src doesnt actually cause mutations by…
affects the function of key proteins
How does HPV work?
Integretes viral DNA into host - permanently transforming host cells.
Doesn’t actually cause mutations but affects the function of key proteins.
Cause of cervical cancer.
How does the HPV vaccine work?
Give the vaccine early on so the virus is identified as forgien
3 hits that are caused by HPV?
E5 Prolonged activation of PDGFR
E6&7 Inhibit pRb and p53
What is the basic function of epidermal growth factor (EGF) pathway?
Cells use this stimulation to stay alive.
At higher levels you get growth and proliferation
Why is EGF receptors important in many cancers? (2)
- EGF important - drives cell proliferation
2. Intrinsic kinase domain leading to down stream signalling pathways (Ras/MAPK and PI3K-PKB)
Mutations in the EGF receptor can cause? (2)
Ligand independance (constituative dimerisation)
and
overexpression - gene amplification
Explain the EGFR pathway…
…see pics.
EGFR -> Ras -> Raf -> MEK -> MEK -> ERK -> Regulation of transcroption
3 types of proto-oncogene changes
- Amplification of WT - when we copy gene to HER 2 the template slips and it gets copied twice (not a mutation, there is just more)
- Val -> Gln - this is charged, unfavorable in the membrane therefore gets dimerised, consitutaively active HER2
- Deletion - creates constituatively active tyrosine kinase (in EGF receptor)
3 types of proto-oncogene changes
- Amplification of WT - when we copy gene to HER 2 the template slips and it gets copied twice (not a mutation, there is just more)
- Val -> Gln - this is charged, unfavorable in the membrane therefore gets dimerised, consitutaively active HER2
- Deletion - creates constituatively active tyrosine kinase (in EGF receptor)
2 Ways to target protooncogenes theraputically
- Block the kinase domain
2. Block ligand binting
E.g. of 2 drugs blocking the kinase domain
erlotinib and gifetanib (for NSCLC)
Small molecule inhibitors blocking ATP binding site on the kinase
e.g. of drug blocking ligand binding
Herceptin
antibody (Ab can only be used for extracellular targets as huge)
When do problems occur with herceptin
if the protein mutates again and the molecule cannot bind
WT HER2 gene is also callled…..
and is amplified in …….. cases of breast cancer
ErbB2
25~30%
HER2+ breast cancer is associated with
faster cell growth
tumour more likey to reoccur
more serious prognosis
How do we detect HER2+ status? (2)
- Immunohistochemistry
- FISH (fluerescent in situ hybridisation) - more sensative than 1.
- HER2-ECD-ELISA (detects cleavage product in serum)
What is the basic action of herceptin?
binding and blocking the activity of HER2
Herceptin is licenced…
originally only for final stage but now sooner.
Provides significant benefit
Problems with herceptin (3)
Not a cure - just slower and remission
Cost
Patient will be on therapy the rest of their lives
How does herceptin decease HER2 signalling? (5)
Need to know basic mechanism, not details
- may induce HER2 R down regulation
- Uncouples Src, Increases PTN
- Induces cell cycle arrest, increased p27
- may increase apoptosis/decrease angiogenisis
- promotes antibody dependent cellulate cytotoxicity (via Fcr and NK cells)
Herceptoin is usaully given with combination of
doxorubicin and cyclophosphamide or paclitaxel
Why give cancer drugs in combo?
Hit multiple pathways using lower doses so fewer sideeffects
s/e problem of herceptin
cardiotoxicity
Is resistance a problem with herceptin?
Yes- cells find other ways to get around the block or there are further mutations so the herceptin is not recognsed
(around 1 year of therapy)
What us Pertuzumab?
A future treatment potentially inihibiting receptor dimerisation
4 future directions for HER 2 breast cancer therapy?
- Pertuzumab
- Recombinant toxins
- Immunotherapy: chimeric proteins - two antibody sights that cross link HER 2 and immune cells
- Immunotherapy: HER 2 vaccines activating CD4+ T cell immunity
Mutations in Ras create…
Ras proteins that are always active
Discrive the ras pathway
**?????**
Where is Ras in the cell?
attached the membrane via a fatty acid modification
What do FTI do? (farnesyl transferase inhibitors)
Inhibit the tethering of Ras to the membrane
Do FTIs work?
No - disappointing trials
because instead of useing farnesyl, geranylgeranyl is added and Ras is still active
But it has potential as a treatment with combination therapy
3 alternative approaches to targeting oncogenes
- Antisense oligonucleotides - HRas, c-Raf - but show little efficacy
- MEK inhibitors - in trial for colon cancer
- Raf inhibitors - approved for renal carcinoma
e.g. of a Raf inhibitor
Nexavar
how is herceptin made1
inserting murine cdr into human iGg
