Sustaining proliferative signalling hallmark of cancer

Question 1

What is the process of EGFR signalling (Epidermal growth factor)?

Answer 1

This regulates growth, proliferation, and survival in mammalian cells.

• Once a ligand (EGF or TGF) has bound to the EGFR receptor, the receptors come together to form homodimers (EGFR) or heterodimers (HER 1,2,3)
• These receptors are then phosphorylated in the intracellular tyrosine kinase domain
• Specific adaptor molecules e.g. Shc, Grb2 or sos permit the activation of RAS, activating the RAS-RAF-MEK-MAPK pathway which causes cekk growth through activation of downstream target genes
• The PI3K pathway can also be activated which stimulates cell growth

Question 2

What are proto-oncogenes?

Answer 2

These are genes that regulate normal cell growth.

Question 3

What is an oncogene?

Answer 3

A mutated proto-oncogene that can cause cancer

Question 4

How is the RAS photo-oncogene turned to an oncogene?

Answer 4

Via a point mutation of a guanine base (G) to a Thymine (T) base
This produces a different amino acid valine instead of glycine and can lead to cancer.
30% of cancers have a RAS gene mutation

Question 5

What is the consequence of a mutated RAS oncogene?

Answer 5

Even when there is no ligand present, if there is a mutation in the RAS gene, it will signal alone and keep firing the pathway- G-protein is stuck on
- This mens the cell cycle is constantly switched on and will cause sustained proliferation.

Question 6

What cancers commonly have a RAS mutation?

Answer 6

Pancreatic, papillary thyroid, colon and non-small cell lung cancer

Question 7

What is the therapeutic target of a cancer with over expressed HER2 genes?

Answer 7

• The HER2 gene is over expressed in 25% of breast cancers- this amplification of HER2 receptors means the cells are growing and dividing in a fast and uncontrolled way and usually cause a poorer prognosis
• In HER2-positive breast cancers, Trastuzumab can be given. This is a humanised monoclonal antibody that blocks the activity of HER2

Question 8

What are predictive biomarkers?

Answer 8

Predictive biomarkers are measures of the likelihood of response of a particular therapy, and allow identification of patients most likely to benefit from a given treatment.
- Important for personalised medicine

Question 9

What is the chromosome abnormality associated with chronic myeloid leukaemia?

Answer 9

The BCR-ABL gene mutation

Question 10

Which cancers are most likely to have the Philadelphia chromosome (BCR-ABL mutation)?

Answer 10

Most cases of chronic myeloid leukaemia (CML)
Some cases of acute lymphoblastic leukaemia (AML) or acute myeloid leukaemia (AML)

Question 11

How is the Philadelphia chromosome formed?

Answer 11

• Chromosome 9 has the ABL gene
• Chromosome 22 has the BCR gene (break point cluster)
  Sections of each of these genes are broken off and translocate (switch places). The chromosome that is formed at chromosome 22 (with the abl gene for Chromosome 9) is the Philadelphia chromosome
• during the fusion, ABL loses its regulatory domain so it constantly emits growth-promoting signals

Question 12

What drug is given in HER2-positive breast cancers?

Answer 12

Trastuzumab

Question 13

What is the consequence of the BCR-ABL fusion gene?

Answer 13

• The hybrid gene is phosphorylated at the Tyr-177 residue which leads to the activation of downstream signalling pathways (e.g. RAS and PI3K/ATK) through GRB2 of the SH2 domain
• This can inhibit cell-cycle arrest and tumour-cell suppressors such as p53= resist apoptosis so cancer cells can survive and continue to proliferate

Question 14

What is used to treat cancers with a BCR-ABL mutation?

Answer 14

• A tyrosine kinase inhibitor e.g. Imatinib
  Inhibit tyrosine kinases from being able to phosphorylate the BCR-ABL fusion at Tyr-177 and therefore prevent downstream signalling that leads to cell division.