oncogenes cooperation and biomarkers Flashcards
can a single oncogene drive cancer formation
no you alsmost always need to loose a tumout suppressor
to feed into enough of the cancer hallmarks, a single oncogene needs to touch a lot of processes
how do receptor kinases cause lots of things to happen
- Well receptor tyrosine kinase has lots of different Pockets.
- So all of these are tyrosine residues and each of them act as separate docks or different scaffolding for different signaling events. S
MYC - an oncogenic TF
MYC is a fairly ubiquitous transcription Factor. It has a function in almost every cell.
- Has lots of different binding domains
○ the most important here is this helix-loop-helix.
○ It works in tandem with its partner Max.
○ They bind together. They then enter the nucleus and they bind to this sequenc called E-boxes
- and it’s involved in a variety of different processes because as a transcription factor, it’s binding not to just one gene its binding to lots of genes and the genes are involved in cell proliferation, differentiation, apoptosis and metabolism.
- By binding with Max it ends up with different specific DNA sequences.
○ MYC can bind to other factors not just max, but Max is its main partner.
how is MYC controlled
the way it’s controlled is by having a very short half-life. (around 20 minutes)
○ so normally it gets activated, gets turned on goes to the nucleus and Once it’s activated it gets Switched Off by being degraded and then once there is no more MYC because it’s been degraded, The signaling is turned off because there is no longer a transcription Factor on the promoter of those genes.
○ So it’s controlled tightly by having a very short window in which it can be active
how many cancer is MYC expressed in
MYC is constitutively and aberrantly expressed in over 70% of human cancers
amplification of MYC
This transcription factor can be amplified
Amplification leads to more MYC
- The more expression of MYC, the more MYC can act as a transcription factor
what contributes to the stabilisation of MYC
Central signaling Pathways, which is Downstream of lots of different things Also contribute to the stabilization of MYC itself. So with these pathways on MYC become stabilized, so we have more MYC there’s more expression, There’s more transcription because MYC is no longer being degraded within that 20-minute window.
examples of how MYC drive cancer
- direct amplification
- pathways leading to deregulation
physiological MYC
transcriptional and post treanscriptional control
dysregulated Myc
collapsed control
when we have e amplification or dysregulation of MYC expression what sort of things is it involved with?
- it’s directly involved in transcription of e2f Target genes.
- We’ve also got this protein biosynthesis.
○ So it’s controlling the regulation of ribosomal proteins.
○ So readying the cells to be able to produce lots of proteins when it’s going to go through cell cycle.
ways to decrease MYC activity
One of the ways that we can do this is directly.
- So on the end where there is binding of MYC and Max, this can be inhibited by these compounds here.
○ omomyc is a small derivative of The Binding sequence that MYC and Max bind to each other
- If you put this into cells it displaces MYC and Max from each other and stops it from binding to DNA.
- You can Target the pathways that stabilized MYC. So the pi3 kinase pathway
- You could inhibit transcription directly.
- And you could inhibit the proteasomal degradation.
None of these are really used in the clinic directly to inhibit MYC apart from omomyc
how can MYC amplification lead to transformation
So MYC amplification can lead to transformation
- can lead to transformation because as a transcription factor it’s involved in the expression of lots of different genes and those different genes are involved in all the pathways that are required to have most of those Hallmarks of cancer.
However, we have these different Pathways that also stabilize MYC expression.
So if you have mutant Ras, this also leads to transformation.
do oncogenes and their pathways cooperate
- oncogenes drive cancer (amplified, mutated, fusions)
- to drive trnasofrmation slots of cell processes need to change
- to do this it is very common that oncogenes cause dysregulated signalling through other oncogenic pathways
- this cooperation doesn’t always synergise
Another way in which we can end up with cooperation with different oncogenic signaling
events is we can have autocrine processes?
- So if you have mutant Ras or activation of the map kinase pathway in general this leads to the expression of different ligands
○ and one example of this is TGF Alpha. - mutant Ras leads to the synthesis of TGF Alpha, it can then be released and it can then signal on to EGF receptors both in the cells themselves but also within the stroma
- Misactivation of the EGF receptor and then lead to a reactivation of the same Pathways that ras is activating
RAS and PI3K pathways
2 branches of growth pathways
- they both drive growth and they both drive surviival
- common to find mutation in one branch and the other branch Because activation of one might not necessarily be enough to drive proliferation of transformation
And it’s also common that if you use inhibitors for one branch,, you’ll find that mutations will occur in the second Branch To offset the fact that you’ve been inhibiting the first one.
receptor tyrosine kinase swapping
mutant EGFR and other RTKssynergise to activate similar pathways
- again commonly occurs in response to inhibiting one RTK
cell signalling at the tumour microenvironment level
what they found was that when you have ras Mutations there is a lots of immune surveillance.
- this is where immune cells are picking up the fact that cells are being transformed and they are removing them.
there’s a lot of tumor cells, They can’t outgrow the amount of immune cell present.
However, when you have both ras and MYC there is an outgrowth of the tumor because there is immune evasion. And there is a lack of cytotoxic cells.
○ There is more tumour promoting cells
The combination of these two events MYC and Ras has the ability to change the micro
environment to make it more favorable by suppressing immune surveillance and increasing
immune evasion.
gene expression profiling
a technique used in molecular biology to query the expression of thousands of genes simultaneously. in the context of cancer, gene expression profiling has been used to more accurately classify tumours. the information derived from gene expression profling often has an impact on predicting the patients clinical outcome and treatment pathway
molecular profiling breast cancer
- 4 main female breast cancer suptypes
- HR+ means that tumour cells have receptors for the hormones oestrogen or progesterone, which can promote the growth of HR+ tumours
- HER2 stands for human epidermal growth factor receptor 2. HER2+ means that tumour cells make high levels of a protein called HER2
HER2
receptor tyrosine kinases which play a role in cell growth, differentiation, and survival
HER2 overexpression or amplification can lead to cell growth and division
- HER2 positive cancers typically treated with targeted therapies such as trastuzumab and pertuzumab
4 main subtypes of breast cancer
- HR+/HER2-
-HR-/HER2+
-HR+/HER2+
HR-/HER2- - LEAST LIKELY SURVIVAL
SUMMARY NOTES
- oncogenes dont just cooperate with tumour suprressor but with others/ oncogenic pathways
- this is again worse in polyclonal tumours
- genomic profiling leads to molecular profiling
- molecular profiling is good for prognosis and treatment decisions
- gene signatures are similar but can be hyper focused
