EGFR family inhibition Flashcards
What other names are given to ErbB-1?
Her1/EGFR
What is ErbB-2 also be known as
Her2/neu
True or false? ErbB-3 has no tryosine kinase activity?
True
How are EGFR signals regulated?
Signal is maintained when in the early endosome, a decision is made.
- It is recycled back to the cell membrane
- It can be broken down via ubiquitination
What three mechanisms can increase the amount of EGFR signalling
Increase the amount of ligand available for binding.
Cross-talk between the receptors
Heterodimerization with other members of the HER family
What is the main way in which EGFRs are targeted?
Antibodies which can block the ligand binding site. Or small molecules which inhibit the ATP binding pocket.
True or false - There is no ligand known to bind ErbB1
False - no ligand known to bind ErbB2
How do antibodies target ErbB2 given that there is no ligand to bind the receptor
Herceptin (Trastuzumab) stimulate an immune response toward the cancer instead. (Only possible in Her2 upregulated breast cancers)
What are the properties of EGFR antibodies
Large proteins (~150KD), have long half life, injected IV once a week, cannot get into the cell compared to small molecules so act on the cell surface
What are the properties of EGFR small molecules
TKI orally available, synthetic chemicals (500Da) with a short half life so have to be taken fairly regularly. Can target molecules regardless of their cellular localisation
Which NSCLC point mutation leads to acquired resistance to EGFR inhibitors
T790M mutation which stops the drug binding
What other mechanisms cause acquired resistance in NSCLC
MET amplification, change to SCLC
Which drug was produced to overcome the T790M mutant dependent acquired drug resistance for NSCLC
Osimertinib
What is EGFRvIII?
A deletion of exons 2-7 and occurs frequently in brain tumours. It becomes a weak form of EGFR, this stops cbl ubiquitination binding to EGFR so even though it produces a weak signal, it is constitutively active.
How does colon cancer become resistant to cetuximab
ERBB2 upregulation EGFR mutation Interaction with BRAF inhibition KRAS Mutation Nuclear EGFR
What causes resistance to EGFRI
Bypass pathways
One of these is ERBB3 which is doing the same thing but bypassing ERBB1 (Ras). Another is MET which induces the PI3K pathway.
What is the main reason why a colon cancer patient will not respond to an EGFR antibody.
Look at their Ras status. If Ras is mutated then there is no point in treating EGFR as the mutation lies downstream.
How does BRAF mutated colon cancer induce unresponsiveness to treatment.
BRAF is downstream of EGFR so EGFR targeted treatments have no effect. BRAF will continue to signal downstream
In colon cancer treated with EGFR inhibitors successfully, after a number of weeks Ras mutants become detectable which is followed by relapse. Why is this>
The time to recurrence is simply the interval required for a subclone to repopulate the lesion.
The original tumour bulk had WT ras which offered some kind of evolutionary benefit to the tumour. Following the inhibition EGFR, Ras WT cells are killed off but the remaining Ras mutant subclones are able to repopulate the tumour bulk.
Why did the chinese, korean, non smoking female population respond well to gifitinib compared to others (for NSCLC)
It was showed that you could get mutations in the tyrosine kinase domain of EGFR. The population that responded well had a much higher number of mutations in the tyrosine kinase domain.
To which cancer are EGFR mutations commonly found
NSCLC
How are NSCLC EGFR mutations targeted and how do they develop resistance
One driver gene induces an oncogenic addiction. TKI has an efficacy as a monotherapy because of this. Resistance builds due to new mutations which prevent the binding of the small molecule.
