Receptor Tyrosine Kinase

Question 1

Mechanism of Activation

Answer 1

Ligand binding to extracellular domain facilitates homo- or hetero-dimerization which activates the intracellular catalytic domain to autophosphorylate tyrosine residues.

Question 2

Stimulation of RasGTPase

Answer 2

Autophosphorylation of RTK following ligand binding causes SH2 domain-containing protein Grb2 to associate. Grb2 also has an SH3 domain which binds proline containing peptides such as Sos. Sos (a GEF) is thus brought to the membrane where it is in close proximity to substrate Ras which it activates.

Question 3

RTK-targeted anti-cancer agent classes (2)

Answer 3

Antibodies: bind to and block the ligand binding site of RTK, preventing signaling.
TKIs: limit the catalytic activity of the intracellular catalytic domain by binding substrate binding pocket which prevents ATP binding to RTK and prevents autophosphorylation.

Question 4

What predicts EGFR-therapy response?

Answer 4

Mutations that change receptor function are better treated with TKIs.
EGFR over-expression or amplification determined by FISH

Question 5

What causes resistance to TKIs? (3)

Answer 5

Patients may develop a new mutation or have selected secondary mutation that prevents the binding of the TKI to the ATP binding pocket.
Another receptor pathway could become mutated, making EGFR irrelevant.
Mutation in downstream signal transducer (ex Ras)