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Flashcards in PROPER targeting downstream RTK's Deck (18)
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1
Q

what is B-Raf mutation key in

A

melanoma

2
Q

what has to happen to a melanocyte to get mutated B-Raf? whats it triggered by

A

triggered by sun exposure

the melanocyte is initiated which gives the individual may nevi 80% of which will be B-RAF mutant= tumours

3
Q

what % of nevi will be BRaf mutant

A

80

4
Q

how can you increase the amount of B-Raf mutations in nevi

A

continuous sun exposure

5
Q

what is the most common B-RAF mutation?

A

valine-to-glutamic acid mutation at residue 600 (V600E) within the protein

6
Q

what does the BRAF mutation produce. what does this do

A

oncogenic protein which has elevated activity and over-activates the MAPK pathway

7
Q

BRAF(V600E) mutations occurs in approx _% of melanomas and ___% of solid tumours

A

60

8

8
Q

what happens to p16 in the braf v600e mutation

A

it increases in the nevus but then decreases at the rapid growth phase

9
Q

what is p16. why does it decrease in expression in the rapid growth phase?

A

a break protein for cell cycle progression

it decreases to allow cell cycle progression and increased proliferation

10
Q

what is the rapid growth phase- where is the tumour at this point? what happens after this

A

radio disease maintained in the epidermis of the skin

then goes to vertical growth phase= metastatic

11
Q

what is a potent mutant BRAF inhibitor?

A

Vemurafenib

12
Q

Vemurafenib MOA?

A

ATP competitive, type 1 small molecule inhibitor of BRAF with antineoplastic activity
selectively binds to ATP binding site of the BRAF(V600E) kinase and inhibits its activity
binding inhibits downstream MAPK signalling

13
Q

what does vemurafenib treat?

A

to treat melanoma with BRAFV600E gene mutation when its spread or cannot be removed with surgery

14
Q

what must the patient have to recieve vemurafenib?

A

mutant BRAF

15
Q

What happens on BRAF inhibitor therapy?

A

initially yields significant reductions in tumour but then resistance occurs

16
Q

how quickly does resistance occur?

A

2-18 months

17
Q

changes which lead to resistance?

A

RTK upregulation

NF1 loss (RAS suppressor)
PTEN loss (PI3K suppressor) 

MAP3K8 which independently activates MEK so RAF inhibition is pointless

BRAF amplification
BRAF splice variants

CRAF upregulation (this increases MEK so BRAF inhibition is pointless)

18
Q

what combination could get round the independent MEK signalling?

A

combine BRAF mutant inhibitors (e.g. Vemurafenib or Dabrafenib) with MEK inhibitor e.g. selumetanib/ Trametinib