Proto-oncogenes and oncogenes

Question 1

What are proto-oncogenes?

Answer 1

Normal genes that regulate cell growth.

Question 2

What are oncogenes?

Answer 2

Mutated or overexpressed proto-oncogenes causing uncontrolled cell proliferation.

Question 3

What is the typical nature of mutations in oncogenes?

Answer 3

Mutations are typically dominant.

Question 4

What are the mechanisms by which oncogenes operate?

Answer 4

Gain of function, gene amplification, chromosomal translocation, loss of tumour suppressor regulation.

Question 5

How many oncogenes have been identified?

Answer 5

~100+ oncogenes identified (e.g., Ras genes ~25% of cancers).

Question 6

What is the Src oncogene?

Answer 6

Discovered in Rous sarcoma virus; encodes v-Src (a tyrosine kinase).

Question 7

How is Src normally regulated?

Answer 7

Src is normally regulated by phosphorylation at Y527 (inactive) and Y416 (active).

Question 8

What happens to Src regulation in cancer?

Answer 8

In cancer (v-Src), this regulation is lost → uncontrolled kinase activity.

Question 9

What are some members of the Src family?

Answer 9

Includes LCK, FYN, LYN, HCK, etc.

Question 10

What are some Src inhibitors?

Answer 10

Dasatinib, bosutinib, saracatinib.

Question 11

What percentage of the human genome contains viral gene fossils?

Answer 11

~8% of the human genome contains viral gene fossils (e.g., endogenous retroviruses).

Question 12

What is an example of an endogenous retrovirus?

Answer 12

HPV (Human Papillomavirus)

HPV has ~100 subtypes and can cause epithelial lesions, cervical and other cancers.

Question 13

What are the oncoproteins associated with HPV?

Answer 13

E6 (inhibits p53), E7 (inhibits pRb), E5 (activates PDGFR).

Question 14

What does the 9-valent vaccine protect against?

Answer 14

The 9-valent vaccine protects against major cancer-causing subtypes of HPV.

Question 15

What is EGFR?

Answer 15

EGFR is a key regulator of cell growth, survival, and proliferation.

Question 16

Which pathways does EGFR activate?

Answer 16

EGFR activates RAS/MAPK, PI3K/Akt, and STAT pathways.

Question 17

How can EGFR be dysregulated in cancer?

Answer 17

Dysregulation can occur via gain-of-function mutation, amplification, chromosomal rearrangement, or autocrine activation.

Question 18

What role does EGFR play in viral entry?

Answer 18

EGFR acts as a co-receptor for HSV-1, HCMV, HCV, and IAV.

Question 19

What are RTK-Targeted Therapies (TKIs)?

Answer 19

Small molecule inhibitors that block ATP binding.

Question 20

What is an example of a TKI used for BCR-ABL in CML?

Answer 20

Imatinib.

Question 21

What are next-generation TKIs?

Answer 21

Dasatinib, Nilotinib, Bosutinib.

Question 22

What are the 1st generation EGFR TKIs?

Answer 22

Gefitinib, Erlotinib.

Question 23

What are the 2nd generation EGFR TKIs?

Answer 23

Afatinib, Dacomitinib.

Question 24

What is the 3rd generation EGFR TKI?

Answer 24

Osimertinib.

Question 25

What is Sunitinib?

Answer 25

A broad-spectrum multi-kinase inhibitor.

Question 26

What is HER2/neu (ERBB2) in breast cancer?

Answer 26

HER2 is a member of the EGFR family that does not need a ligand to activate. ## Footnote Overexpressed in ~15-30% of breast cancers.

Question 27

How is HER2 diagnosed?

Answer 27

Diagnosis can be made via IHC (0–3+), FISH (gene amplification), or ELISA (serum detection).

Question 28

What is HER2-targeted therapy?

Answer 28

Trastuzumab (Herceptin) blocks HER2 activity and signals an immune response (ADCC). ## Footnote It carries a risk of cardiotoxicity and has resistance mechanisms such as PIK3CA mutations and PTEN loss.

Question 29

What are the advancements in HER2-targeted therapy?

Answer 29

Advancements include combination therapy with chemotherapy, antibody-drug conjugates, next-gen TKIs (e.g., Lapatinib for brain metastases), HER2 vaccines, and bispecific antibodies.

Question 30

What are Ras oncogene mutations?

Answer 30

Ras mutations at G12 or Q61 lead to constitutive activation and are highly prevalent in pancreatic (90%), colorectal (45%), and AML (30%) cancers.

Question 31

Why is Ras a hard target for therapy?

Answer 31

Ras is a hard target due to its essential role in normal cells.

Question 32

What are the strategies for targeting Ras?

Answer 32

Strategies include Farnesyltransferase Inhibitors (FTIs) with limited success and MEK/Raf inhibitors (e.g., Sorafenib, CI-1040).