Melanoma MAPK Flashcards
How many people in the US get melanoma each year?
> 70,000
How many people die from melanoma each year?
8,800
How much more likely are white people to development melanoma than blacks?
10 times
Since 1992, when was the first drug to be FDA approved for melanoma?
2011
How many cancers is Braf mutated in?
50%
What found that Braf was commonly mutated in melanoma?
Human genome project
What Ras mutation is commonly mutated in skin cancer?
N-Ras
How are Ras mutations constitutively active?
Locked into a GTP-active form
Where are the mutations in Raf?
In the kinase domain
What are common mutational effects in the EGFR pathway?
Receptor dimerisation
Intracellular phosphorylation of the receptor
Transphosphorylation of components of the signalling pathway
Why do you not find patients with Braf and Nras mutations?
Since they are in the same pathway they are epistatic
What are Nras mutations?
Undruggable
Under physiological conditions, what does Raf function as?
A dimer
How is the MAPK signalling pathway regulated?
Negative feedback loops:
- ERK inhibits Raf
- ERK inhibits SOS
- ERK inhibits the EGFR
- ERK induces SPRY which inhibits GRB2
In cancer, why do Rafs not need to do to function?
Dimerise
Since Raf is constitutively active, what it is independent of?
The signalling components above it meaning the negative feedback loops have no effect
Why is PLX4720 so selective for Braf V600E?
Binding site overlaps the ATP binding site
PLX4720 binds preferentially to the active conformation
As Braf V600E is in a permanent active conformation it binds better
Mutations may alter the Raf-selective pocket in such a way that it favours PLX4720 binding
What was the first successful Braf V600E drug?
Vemurafenib
What did they used to test if vemurafenib was working?
PET scans
How do PET scans work?
They are radioactive glucose transfers so it detects metabolically active tissue
What happens to the drug trial patients after 23 weeks of vemurafenib?
Developed resistance
When conducting clinical trials with personalised medicine, what is it important to do?
Make sure they have the mutation you are trying to target
What is the long term side effect of vemurafenib?
The development of SCC in pre-existing clones of cells, with Ras mutations
How do Braf inhibitors induce resistance and cause SCC?
The Braf dimerises with C-Raf through:
- Having more Ras
- Amplification of C-Raf
What are the Raf dimerisation-dependent resistance mechanisms?
NRAS mutations
Splice variant
CRAF overexpression
How does splice variation induce Braf inhibitor resistance?
Produce a mutant Braf called p61 which still binds the drug but also can dimerise with WT Braf to promote ERK signalling
How can you overcome dimerisation-dependent Raf resistance mechanisms?
By preventing paradoxical activation
What are the non-dimerisation dependent Raf resistance mechanisms?
Get mutations in downstream components of the ERK pathway e.g. MEK
Bypass Raf by activation of COT which activates MEK
How can you overcome resistance?
Using combination therapies, e.g. Raf and MEK inhibitors
Give an example of a MEK inhibitor?
Trametinib
What are the MEK inhibitor resistance mechanisms?
Mutations in MEK
Braf amplifications which increase pool of active MEK1 and 2
Kras amplification increases pool of active MEK1 and 2 as well as activates other Ras effectors
What are the future directions of malignant melanoma therapies?
ERK1/2 inhibitors
Co-Targeting the AKT/mTOR pathway
Target MAPK and PI3K pathway in combination with PD-1 blockades
Intermittent Braf inhibitor therapy
What is intermittent Braf inhibitor therapy?
Give the drug for a short period of time, wash it off and ERK activity increases really high, so high that it drives senescence and cell death
Keep repeating process
The drug isn’t there for long enough to induce resistance
