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PA40157 Cancer > Proto-oncogenes to oncogenes > Flashcards

Proto-oncogenes to oncogenes Flashcards

(80 cards)

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1
Q

How are proto-oncogenes converted to oncogenes?

A

Gain of function mutation

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2
Q

What are the three types of gain of function mutations that can occur?

A

Point mutation
Gene amplification
Chromosomal translocation

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3
Q

What is a point mutation?

A

Change of a base which changes the amino acid which changes the structure/function of a protein

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4
Q

what is gene amplification?

A

Where there is a slip and a copy of the template again which expresses more protien

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5
Q

What is chromosomal translocation?

A

Bits of chromosomes swap over

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6
Q

Proto-oncogenes are more susceptible to what?

A

Mutations

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7
Q

What is Src tyrosine kinase?

A

An enzyme which phosphorylates on the tyrosine residue

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8
Q

What are the 3 Src domains?

A

SH3 domain
SH2 domain
Kinase domain

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9
Q

What does the SH3 Src domain do?

A

Binds proline residues

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10
Q

What does the SH2 Src domain do?

A

Binds phosphorylated tyrosine residues

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11
Q

What does the kinase domain do in Src?

A

Phosphorylates the tyrosine residue

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12
Q

In resting cells, Src is what?

A

Phosphorylated

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13
Q

What happens when Src is phosphorylated?

A

The molecule folds up such that there is intra-molecular binding and the SH2 domain binds to the phosphorylated tyrosine

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14
Q

What happens when Src is folded up?

A

You can’t get any substrate in the active site of the kinase and therefore the molecule is inactive

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15
Q

Src sits in the cytoplasm folded up until what?

A

A receptor is activated and sends out a growth signal

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16
Q

What else happens when a receptor is activated?

A

you get a phosphatase being activated which dephosphorylates that tyrosine

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17
Q

What happens when Src unfolds?

A

SH3 binds proline
SH2 binds tyrosine residue
Kinase finds its substrate and sends off a growth signal

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18
Q

What happens in oncogenic Src?

A

It loses the C terminal tyrosine so it can’t get phosphorylated and it can’t fold up.
Constitutive activation.

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19
Q

What happens with constitutive activation of Src?

A

Cells keep growing, round up, less cell-cell contact, cells break off more easily

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20
Q

Mutations in Src correlate with what?

A

Metastatic potential

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21
Q

What is HPV?

A

an oncogenic DNA virus

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22
Q

What does HPV do?

A

Integrates viral DNA into host genome. Permanently transforms host cells.

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23
Q

What does HPV cause?

A

Cervical cancer

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24
Q

What does the E5 subunit of HPV do?

A

Causes prolonged activation of PDGFR (growth factor receptor)

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25
What do the E6 and E7 subunits of HPV do?
Inhibit pRb and p53 (tumour suppressor proteins)
26
Is Src a proto-oncogene or a tumour suppressor gene?
Proto-oncogene
27
A lot of cells use what family to control their growth?
EGF family
28
Are EGFRs proto-oncogenes or tumour suppressor genes?
Proto-oncogenes
29
Why is EGF an important growth factor?
It drives cell proliferation
30
What does the intrinsic kinase domain of EGF lead to?
Activation of downstream signalling pathways-Ras/MAPK (cell growth) and PI3K-PKB (pro survival, anti apoptotic factor)
31
Mutations in EGF receptors can cause what?
Constitutive activation
32
When EGFRs are constitutively active, they are what?
Ligand independent
33
What makes EGFR constitutively active?
Two chains becoming constitutively dimerised which makes the receptor active even in the absence of growth factor ligand
34
What happens in the HER2 case?
Overexpression of the gene from gene amplification
35
What is the sequence for EGFR signalling?
EGFR--> SOS-->Ras-->Raf-->MEK-->ERK-->c-fos
36
Is EGFR a homo or hetero dimer?
Homodimer
37
When does EGFR normally dimerise?
In the presence of a ligand
38
What is Ras?
GTPase
39
What is Ras bound to in resting state?
GDP
40
What does recruitment of SOS allow?
Exchange from GDP to GTP and Ras gradually hyrdolyses to GDP again
41
What is a proto-oncogene?
A normal gene that could become an oncogene due to mutations or increased expression. they code for proteins that help to regulate cell growth and differentiation
42
What are the EGFR family called in mice?
EGFR
43
What are the EGFR family called in humans?
``` HER family (Human epidermal growth receptor) or ERB ```
44
How many HER receptors are there?
4
45
What happens when there are mutations in the wild type EGF receptor?
Lose the extracellular ligand portion of the receptor
46
What happens to stabilise the receptor?
the kinase domain in the signalling chain dimerises
47
What happens when the signalling chain of EGFR dimerises?
The chains autophosphorylate and transphosphorylate
48
What happens in HER2 if gene amplification occurs?
Wild type receptor, just too much gene and too much protein. it becomes very sensitive to low levels of growth factor
49
What happens when there is a HER2 amino acid mutation?
Valine point mutation to glutamine. Tow chains dimerise to reduce disruption of the membrane. activates the kinase
50
How do Iressa and Tarceva work?
Block the ATP binding site in the kinase domain. There is no source of phosphate so it can't phosphorylate and so there is no downstream signal
51
Why is Iressa only effective in around 10% of patients?`
It binds to a certain mutated form of the receptor
52
How does Herceptin work?
It blocks ligands binding to HER2 (by binding to HER2 itself)
53
What gene is amplified in 25-30% of metastatic cancers?
HER2 (ErB2)
54
Where else are HER2 receptors expressed?
The heart
55
What do we screen for in breast cancers?
HER2+, oestrogen dependent, progesterone dependent (or triple negative)
56
What techniques are used to screen breast cancers?
Immunohistochemistry FISH (fluorescent in situ hybridisation) ELISA
57
What is Herceptin (Trastuzumab)?
Humanised monocloncal antibody which recognises HER2
58
How is Herceptin constucted?
Inserting murine CDR into human IgG
59
What was Herceptin originally licensed for and what is it used for now?
Final stage aggressive HER2 cancer | Now also available to early stage patients
60
Why are antibodies a good treatment choice?
They bind specifically to individual proteins
61
Which part of the antibody will attract T cells and NK cells and kill off the target cell by apoptosis?
Free Fc portion
62
What are the possible mechanisms of action for Herceptin?
1. Decreases activation of signalling pathways 2. Induce downregulation of the receptor 3. Uncouples Src activation 4. Increases PTEN which switches off PI3 kinase pathway (survival) 5. Induces cell cycle arrest by increasing cyclin dependent kinase inhibitors (p27) 6. Increase apoptosis of the cell 7. Decrease angiogenesis 8. Promotes antibody dependent cellular cytotoxicity (ADCC) (viaFcR on NK cells)
63
What is Herceptin usually given in combination with?
Doxorubicin and cyclophosphamide or paclitaxel
64
What are the issues with Herceptin?
Patients treated for 1 year but build up resistance. | Potential cardiotoxicity-HER2 important in ventricular development
65
How does Pertuzumab work?
Inhibits receptor dimerisation
66
What is Ras and what does it do?
GTPase so hydrolyses GTP to GDP-->causes phosphorylation of Raf (and activation)
67
What kind of mutations are found in Ras in many human tumours?
Activating mutations
68
What percentage of pancreatic, colo-rectal and acute myeloid leukarmias have activating mutation in Ras?
90% 45% 30%
69
What do mutations in Ras proteins cause?
Constant activation of Ras
70
What effect will Iressa and Tarceva have on cancers with Ras mutations?
No effect- they will be pointless because they work upstream of the mutation. You can block the receptor but Ras would still sit in the membrane and signal.
71
What strategies would be needed to treat Ras mutated cancers?
Either block Ras itself or block further down the pathway at Raf or MEK
72
Why is it difficult to develop a small molecule inhibitor for Ras?
Ras is not a kinase, so the active site is different
73
Where does Ras have to sit to be active?
In the membrane
74
How can you block Ras activity?
Block it from membrane localisation so it cannot come into contact with its substrate
75
What tethers Ras to the membrane?
Fatty acid modification
76
What were developed to inhibit tethering of Ras to the membrane?
Farnesyl transferase inhibitors (peptidomimetics)
77
What effect did Farnesyl transferase inhibitors have in mice?
Good response
78
Why did Farnesyl transferase inhibitors fail in clinical trials?
geranylgeranyl fatty acids were added instead of farnesyl which meant that Ras was still active. If you inhibited both enzymes it made it too toxic
79
Why weren't animals good predictive models for farnesyl transferase inhibitors?
Animals only have the farnesyl group and not the geranylgeranyl group
80
What are the alternative approaches to targetting Ras mutations?
Antisense olignonucleotides- little efficacy MEK inhibitors-PI trials colon cancer Raf inhibitors-approved for renal carcinoma also blocks VEGF and PDGFR

PA40157 Cancer (10 decks)

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