L7 - Oncogene co-operation and biomarkers

Question 1

Myc: what is it, what does it do, what does it typically associate with, how is it normally regulated, how many cancers involve it, and what clinical application can possibly be taken against it?

Answer 1

Oncogenic transcription factor

Involved in cell proliferation, differentiation, metabolism, and apoptosis (various parts in tumour growth)

Normally dimerises with Max and binds to E-boxes(? whatever that)

Half-life of ~20 mins, rapid degradation by the proteasome

> 70% of cancers involve its constitutive activation, this is due to it losing its death timer and being amplified due to its survival and production (?), resulting in it activating not only its high-affinity targeting genes but also its low-affinity targeting genes which often results in tumorigenesis

Though none have clinical use currently, potentially targetting its dimerisation with Max, targeting myc itself, targeting myc mRNA translation, or targeting myc mRNA generation

Question 2

Hourglass model of cellular signalling: what is it and why is it beneficial?

Answer 2

• Lots of ligands/receptors
• Few kinases
• Lots of gene/phosphorylation targets

Allows a wide range of activators that cause funnelling into the same processes which can then cause signal amplification

Question 3

Oncogenic pathways: do they always cooperate?

Answer 3

Not always (ie mutant KRAS and myc have been found in lung cancer mouse models to have slower tumour formation than just KRAS alone)

Does a lot of the time: autocrine TGF signalling, MAPK/PIP3-Akt pathways, RAS/myc

Question 4

Autocrine signalling: how can it impact cancer?

Answer 4

Autocrine signalling from molecules like TGF-beta can cause co-operation of oncogenic pathways as well as signal diversification

Question 5

MAPK/PIP3-Akt pathways

Answer 5

Both activated by Ras

• PIP3 gets phosphorylated into PIP2 by PI3K (pTEN causes the reverse process), PIP2 then goes on to cause mTOR activation downstream - mutations in PI3K and pTEN are common cancer causing mutations as they are proto-oncogenes/TSGs respectively
• Ras activates RAF which then causes ERK activation downstream which has cell proliferation/survival effects - BRAF is a common oncogene as mutations in it can cause its constitutive activation without Ras

Question 6

RTK swapping/doubling down

Answer 6

Inhibiting one RTK pathway may cause other pathways to take over its job, resulting in failing treatment against tumours

Question 7

HR/HER2: what is it, how do they present in breast cancer, what survival rates do they cause. and why?

Answer 7

HER2 (human epidermal growth factor receptor 2) is receptor tyrosine kinases (RTKs) which play a role in cell growth, differentiation, and survival.

HER2 overexpression or amplification can lead to cell growth and division

We know the cause????

Rewatch leccy or don’t idc

Question 8

Genomic profiling

Answer 8

Leads to more specific molecular profiling

Question 9

Molecular profiling

Answer 9

Good for prognosis and treatment decisions

Gene signatures are similar but can be hyper focused