Tyrosine Kinase Inhibitors

Question 1

What protein function inhibitor drugs target a unique aspect of specific cancer type?

Answer 1

L-asparaginase

Imatinib

Question 2

What protein function inhibitors are less specific and exploit overexertion of a particular protein?

Answer 2

Erlotinib

Gefitinib

Question 3

What protein function inhibitors are targeting rapidly dividing cells and/or angiogenesis?

Answer 3

Bortezomib
Vorinostat
Sorafenib
Sunitinib

Question 4

What are the types of Tyrosine kinase inhibitors?

Answer 4

• Some are Signal Transduction Inhibitors
• Inhibitors of:
  1. Bcr-Abl
  2. EGFR
  3. HER2
  4. PDGF-R, VEGF-R (not talking about these)

Question 5

What drugs are tyrosine kinase inhibitors of Bcr-Abl? What cancer type are they used for?

Answer 5

-Bosutinib
-Dasatinib
-Imatinib
-Nilotinib
CML (chronic myeloid leukemia)

Question 6

What drugs are tyrosine kinase inhibitors of EGFR? What type of cancer are they used for?

Answer 6

-Cetuximab
-Erlotinib
-Gefitinib
-Panitumumab
Epithelial derived (lung, pancreas, head, neck, breast, prostate, colon, stomach, ovaries, brain)

Question 7

What drugs are tyrosine kinase inhibitors of HER2? What cancer are these used for?

Answer 7

-Pertuzumab
-Trastuzumab [Ado-Trastuzumab, Emtansine]
Breast cancer

Question 8

What drugs are tyrosine kinase inhibitors of PDGF-R, VEGF-R? (not talking about these) What are these used for?

Answer 8

-Pazopanib
-Sorafenib
-Sunitinib
Many different cancers - including glioblastoma, hepatocellular carcinoma, renal cell carcinoma

Question 9

What doe the -nib ending mean?

Answer 9

Signal transduction inhibitor

Question 10

What are some important general concepts about tyrosine kinases?

Answer 10

• TKs are important regulators of intracellular signal transduction pathways responsible for development and multicellular communication
• TKs phosphorylate tyrosine residues
• > 50% of known receptor TKs have been found either mutated or overexpresssed forms that are associated with malignancies
• Both STI and antibodies have been designed to interfere with the action of specific tyrosine kinases

Question 11

What drugs target c-kit and fight GIST (gastrointestinal stromal tumor) cancer?

Answer 11

• Dasatanib
• Imatinib
• Nilotinib
• Sunitinib

Question 12

What is the MOA for Cetuximab/Panitumumab?

Answer 12

Inhibitors of EGFR

• Epithelial Growth Factor Receptor (EGFR) tyrosine kinase is overexposed in a large number of epithelial-derived cancers
• These drugs are monoclonal antibodies directed against EGFR
• These drugs prevent actions of EGFR, as well as identifying cells expressing the receptor as foreign (making them targets of cell mediated immunity)

Question 13

What are the side effects of cetuximab/panitumumab?

Answer 13

• Side effects common to Abs:
• –Infustion/hypersensitivity reactions: fever, muscle aches, headaches, rashes, anaphylaxis, infusion reactions
• –Mouse (MO)»_space; Chimeric (XI) > Humanized (ZU) for HAMA reaction
• –Infections
• –Unknown effects on immunization, carcinogenesis, mutagenesis, impairment of fertility, pregnancy, nursing infants (human IgG is secreted in milk)
• Unique toxicities affect skin (rash, photosenstivity, necrotizing fasciitis) and lung (interstitial lung disease)

Question 14

How do HER1 inhibitors affect cancer?

Answer 14

Human Epithelial Growth Factor Receptor 2 tyrosine kinase is overexposed in a large number of aggressive breast cancers
-Mostly used for breast cancers that you can’t use doxorubicin to target!!

Question 15

What is the mechanism of trastuzumab?

Answer 15

Binding of the antibody interferes with HER2 signaling, and identifies the HER2-overexpressing cells as foreign, so that they can be destroyed by the immune system!

Question 16

What is the mechanism of action of Perfuzumab?

Answer 16

It’s considered the first antineoplastic DIMERIZATION INHBIITOR (new drug class) ; it prevents HER2 from dimerizing with other HER receptors (can’t function)

Question 17

What is the mechanism of action of Ado-Trastuzumab Emtansine?

Answer 17

It is internalized and undergoes lysosomal degradation to form 2 parts:

1. Trastuzumab
2. DM1 - a small molecule inhibitor that disrupts microtubule networks by binding tubulin

Question 18

What is the resistance mechanism developed against HER2 inhibitors?

Answer 18

Altering HER2 so that the antibody doesn’t recognize its target!!

Question 19

What are the side effects associated with Trastuzumab (HER2 tyrosine kinase inhibitor)?

Answer 19

1. Side effects common to antibodies:
   - Infustion/hypersenstiviity reactions: fever, muscle aches, headaches, rashes, anaphylaxis, infusion reaction
   - Mouse (MO)»_space; chimeric (XI) > humanized (ZU) for HAMA reaction
   - Infectioins
   - Birth defects/fetal loss
   - Unknown effects on immunization, carcinogenesis, mutagenesis, impairment of fertility, nursing infants
2. Unique toxicities among antibodies include ventricular dysfunction and congestive heart failure