YW - Specific Drugs for Treating Cancer

Question 1

What are examples of specific drugs used to treat cancer? (5)

Answer 1

• BCR-ABL inhibitors (e.g., Gleevec)
• EGFR inhibitors
• BRAF inhibitors
• PD-1/PD-L1 inhibitors
• VEGF inhibitors

Question 2

What is the Philadelphia chromosome? (3)

Answer 2

• A chromosomal abnormality associated with cancer
• Present in all cases of chronic myeloid leukemia (CML) and 10% of acute lymphocytic leukemia (ALL)
• Results from a t(9;22)(q34;q11) translocation

Question 3

What do p and q represent in chromosomal translocations?

Answer 3

p: short arm of the chromosome

q: long arm of the chromosome

Question 4

How does Gleevec (Imatinib) work in treating leukemia? (4)

Answer 4

• Targeting the Activation Loop: Gleevec binds to the active site of the Bcr-Abl kinase domain, specifically targeting the activation loop.
• Inhibiting Kinase Activity: By binding to this critical region, Gleevec prevents the phosphorylation of key tyrosine residues within the activation loop.
• Blocking Signal Transduction: This inhibition disrupts the downstream signaling pathways that promote cell proliferation, survival, and transformation.
• Inducing Apoptosis: In some cases, Gleevec can trigger apoptosis, or programmed cell death, in cancer cells.

Question 5

Why do some patients develop resistance to Gleevec? (3)

Answer 5

Mutations: T315I mutation in the BCR-ABL kinase domain reduces Gleevec binding.

Gene Amplification: Increased production of BCR-ABL overwhelms inhibition.

Overexpression: Higher BCR-ABL levels due to altered regulation or mRNA stability.

Question 6

How are second-generation TKIs used to overcome Gleevec resistance? (3)

Answer 6

• Examples: Dasatinib, Nilotinib
• Broader spectrum: Target multiple conformations of the BCR-ABL kinase domain.
• Effective against most resistance mutations (except T315I).

Question 7

What is SGX393, and why is it important? (3)

Answer 7

• A third-generation TKI targeting the T315I mutation in BCR-ABL.
• Demonstrates superior potency against resistant mutations.
• Can be combined with second-generation TKIs for enhanced efficacy.

Question 8

What is the role of EGFR in cancer? (3)

Answer 8

1) Activated by ligands like EGF or TGF-α, leading to dimerization and autophosphorylation.

2) Promotes downstream signaling pathways (e.g., MAPK) for cell proliferation and survival.

3) Targeted by therapies like:

• Cetuximab (monoclonal antibody blocking ligand binding)
• Gefitinib (small molecule inhibiting the kinase domain)

Question 9

How have monoclonal antibodies evolved as targeted therapies? (4)

Answer 9

1) Fully Mouse Antibodies:

• 100% mouse protein; highly immunogenic in humans.
• Rapid clearance and potential immune reactions.

2) Chimeric Antibodies:

• Mouse antigen-binding region; human constant region.
• Reduced immunogenicity compared to fully mouse antibodies.

3) Humanized Antibodies:

• Only antigen-binding regions are mouse-derived; rest is human.
• Further reduces immunogenicity and improves efficacy.

4) Fully Human Antibodies:

• Entirely human; minimal immune response risk.
• Produced via techniques like phage display and transgenic mice.

Question 10

Second-Generation EFGR Inhibitors (2)

Answer 10

Irreversible Binding: These inhibitors, such as afatinib and dacomitinib, form irreversible covalent bonds with the ATP-binding site of EGFR. This prevents the binding of ATP, a crucial molecule for kinase activity.

Broader Spectrum: Second-generation inhibitors often target multiple members of the HER family, including HER2, HER3, and HER4, providing a broader spectrum of activity.

Question 11

Third-Generation EGFR Inhibitors (2)

Answer 11

Specific Targeting of Resistant Mutations: Third-generation inhibitors, like osimertinib, are specifically designed to target the T790M mutation, a common mechanism of resistance to first- and second-generation EGFR inhibitors.

Enhanced Potency: These drugs exhibit increased potency and selectivity for EGFR, making them more effective in overcoming resistance.

Question 12

What is the significance of the BRAF V600E mutation in melanoma? (3)

Answer 12

• Prevalence: Found in 40-60% of cutaneous melanomas.
• Dominant Mutation: Accounts for ~90% of BRAF mutations in melanoma.
• Effect: Constitutively activates the MAPK pathway, driving uncontrolled cell growth and proliferation.

Question 13

How does Vemurafenib target the BRAF V600E mutation? (3)

Answer 13

• Vemurafenib is a small molecule inhibitor designed for the BRAF V600E mutant protein.
• It binds to the ATP-binding site, blocking phosphorylation activity.
• This inhibits downstream signaling, disrupting pathways that drive tumor growth.

Question 14

How does the BRAF-V600E mutation affect the MAP kinase pathway, and how is it targeted? (2)

Answer 14

• BRAF-V600E Mutation: Constitutively activates the MAP kinase pathway, driving uncontrolled cell proliferation.
• BRAF Inhibitors: Drugs like Vemurafenib block this mutation, inhibiting the MAP kinase pathway to control cell growth.

Question 15

What mechanisms cause resistance to BRAF inhibitors? (4)

Answer 15

NRAS mutations: Reactivate the MAPK pathway.

c-RAF amplification: Compensates for mutant BRAF inhibition.

MEK mutations: Activate the pathway downstream of BRAF.

RTK activation: Bypasses BRAF-MEK-ERK signaling.