Receptor Tyrosine Kinase

Question 1

mechanism of receptor tyrosine kinase activation.

Answer 1

RTK activation is driven by ligand binding –> dimerization

-can homodimerize or heterodimerize to activate signaling depending on ligand

Question 2

Epidermal growth factor receptor (EGFR) key downstream signaling event

Answer 2

Ras activation

- stimulates proliferation of cell

Question 3

Ras proteins

Answer 3

GTP binding protein.
membrane bound switches that are regulated by GAPs and GEFs

• GDP bound: inactive
• GTP bound: active

Question 4

molecular mechanism of stimulation of ras GTPase by RTKs

Answer 4

1. ligand binds to RTK
2. SH2 and Grb2 (adaptor) binds to activated receptor by PM
3. Sos (Ras GEF) gets recruited, its proximity with membrane bound Ras…
4. Activates Ras
   - (sos can activate even in absence of RTK stim)

Question 5

two main classes of RTK-targeted anti-cancer agents

Answer 5

EGFR as therapeutic target in cancer using 2 agents:

1. TKI’s
2. antibodies:
   Gefitinib
   Cetuximab

Question 6

mechanism of action of RTK-targeted anti-cancer agent:

Cetuximab

Answer 6

Anti-EGFR cetuximab blocks ligand binding site

• -> prevent dimerization
• -> prevents proliferation

Question 7

mechanism of action of RTK-targeted anti-cancer agent:

Gefitinib

Answer 7

Anti-EGFR gefitinib blocks ligand binding and EGFR kinase activity

• -> blocks phosphorylation activation of receptor and intracellular messengers
• -> stops downstream signaling

Question 8

mechanism of action of RTK-targeted anti-cancer agent:

TKIs

Answer 8

very specific (too specific)
specific to each tyrosine kinase

blocks ATP binding site –> kinase dies

Question 9

tumor cell characteristics that predict clinical response to EGFR-targeted therapeutics

Answer 9

Individuals with mutant EGFR TK is more active and more potently inhibited by gefitinib (bound with higher affinity)

Question 10

mechanism of resistance to TKI’s such as EGFR inhibitors.

Answer 10

Acquired resistance-A secondary mutation in EGFR causes individuals who initially benefited from therapy, but then acquire resistance to antibodies
=(

the 2nd mut block inhibitor binding to kinase activation site