oncogenes cooperation and biomarkers

Question 1

can a single oncogene drive cancer formation

Answer 1

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

Question 2

how do receptor kinases cause lots of things to happen

Answer 2

• 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

Question 3

MYC - an oncogenic TF

Answer 3

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.

Question 4

how is MYC controlled

Answer 4

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

Question 5

how many cancer is MYC expressed in

Answer 5

MYC is constitutively and aberrantly expressed in over 70% of human cancers

Question 6

amplification of MYC

Answer 6

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

Question 7

what contributes to the stabilisation of MYC

Answer 7

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.

Question 8

examples of how MYC drive cancer

Answer 8

• direct amplification
• pathways leading to deregulation

Question 9

physiological MYC

Answer 9

transcriptional and post treanscriptional control

Question 10

dysregulated Myc

Answer 10

collapsed control

Question 11

when we have e amplification or dysregulation of MYC expression what sort of things is it involved with?

Answer 11

• 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.

Question 12

ways to decrease MYC activity

Answer 12

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

Question 13

how can MYC amplification lead to transformation

Answer 13

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.

Question 14

do oncogenes and their pathways cooperate

Answer 14

• 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

Question 15

Another way in which we can end up with cooperation with different oncogenic signaling
events is we can have autocrine processes?

Answer 15

• 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

Question 16

RAS and PI3K pathways

Answer 16

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.

Question 17

receptor tyrosine kinase swapping

Answer 17

mutant EGFR and other RTKssynergise to activate similar pathways
- again commonly occurs in response to inhibiting one RTK

Question 18

cell signalling at the tumour microenvironment level

Answer 18

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.

Question 19

gene expression profiling

Answer 19

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

Question 20

molecular profiling breast cancer

Answer 20

• 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

Question 21

HER2

Answer 21

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

Question 22

4 main subtypes of breast cancer

Answer 22

• HR+/HER2-
  -HR-/HER2+
  -HR+/HER2+
  HR-/HER2- - LEAST LIKELY SURVIVAL

Question 23

SUMMARY NOTES

Answer 23

• 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