EGFR family inhibition

Question 1

What other names are given to ErbB-1?

Answer 1

Her1/EGFR

Question 2

What is ErbB-2 also be known as

Answer 2

Her2/neu

Question 3

True or false? ErbB-3 has no tryosine kinase activity?

Answer 3

True

Question 4

How are EGFR signals regulated?

Answer 4

Signal is maintained when in the early endosome, a decision is made.

1. It is recycled back to the cell membrane
2. It can be broken down via ubiquitination

Question 5

What three mechanisms can increase the amount of EGFR signalling

Answer 5

Increase the amount of ligand available for binding.
Cross-talk between the receptors
Heterodimerization with other members of the HER family

Question 6

What is the main way in which EGFRs are targeted?

Answer 6

Antibodies which can block the ligand binding site. Or small molecules which inhibit the ATP binding pocket.

Question 7

True or false - There is no ligand known to bind ErbB1

Answer 7

False - no ligand known to bind ErbB2

Question 8

How do antibodies target ErbB2 given that there is no ligand to bind the receptor

Answer 8

Herceptin (Trastuzumab) stimulate an immune response toward the cancer instead. (Only possible in Her2 upregulated breast cancers)

Question 9

What are the properties of EGFR antibodies

Answer 9

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

Question 10

What are the properties of EGFR small molecules

Answer 10

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

Question 11

Which NSCLC point mutation leads to acquired resistance to EGFR inhibitors

Answer 11

T790M mutation which stops the drug binding

Question 12

What other mechanisms cause acquired resistance in NSCLC

Answer 12

MET amplification, change to SCLC

Question 13

Which drug was produced to overcome the T790M mutant dependent acquired drug resistance for NSCLC

Answer 13

Osimertinib

Question 14

What is EGFRvIII?

Answer 14

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.

Question 15

How does colon cancer become resistant to cetuximab

Answer 15

ERBB2 upregulation
EGFR mutation
Interaction with BRAF inhibition 
KRAS Mutation
Nuclear EGFR

Question 16

What causes resistance to EGFRI

Answer 16

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.

Question 17

What is the main reason why a colon cancer patient will not respond to an EGFR antibody.

Answer 17

Look at their Ras status. If Ras is mutated then there is no point in treating EGFR as the mutation lies downstream.

Question 18

How does BRAF mutated colon cancer induce unresponsiveness to treatment.

Answer 18

BRAF is downstream of EGFR so EGFR targeted treatments have no effect. BRAF will continue to signal downstream

Question 19

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>

Answer 19

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.

Question 20

Why did the chinese, korean, non smoking female population respond well to gifitinib compared to others (for NSCLC)

Answer 20

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.

Question 21

To which cancer are EGFR mutations commonly found

Answer 21

NSCLC

Question 22

How are NSCLC EGFR mutations targeted and how do they develop resistance

Answer 22

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.