Signal Transduction Pathway Targeting Extra Reading

Question 1

What do Iressa, Glivec and Herceptin have in common?

Answer 1

They are all molecular therapeutics targeted to deregulated signal transduction pathways.

Iressa: EGFR tyrosine kinase inhibitor (ATP binding?)
Glivec: Bcr-Abl inhibitor
Herceptin: HER2 extracellular domain.

Question 2

Iressa

Answer 2

EGFR tyrosine kinase inhibitor (ATP?)

Question 3

Glivec:

Answer 3

Bcr-Abl inhibitor

Question 4

Herceptin

Answer 4

HER2 extracellular domain.

Question 5

As most cancers are likely to be driven by the combined effects of several different oncogenes and tumour-suppressor genes (CSC hypothesis etc), it is likely that targeting any one of the deregulated pathways will be sufficient to have what type of therapeutic effect?

Answer 5

A cytostatic, rather than cytotoxic effect. Likely to stop any more tumour growth but not to kill the tumour cells.

Question 6

Farnesyl transferase inhibitors are used to treat mutations to which aspect of the Ras -> MAPK kinase pathway?

Answer 6

Ras.
Prevent the post-translational modification and membrane localisation of Ras = block the proliferative signal transduction.

Question 7

How do FTIs work?

Answer 7

Prevent the post-translational modification and membrane localisation of Ras = block the proliferative signal transduction.

Ras -> MAPK etc.

Question 8

Lonafarib is an example of

Answer 8

FTIs.
Prevent the post-translational modification and membrane localisation of Ras = block the proliferative signal transduction.

Question 9

Tipifarnib is an example of

Answer 9

Prevent the post-translational modification and membrane localisation of Ras = block the proliferative signal transduction.

Question 10

Signal transduction pathway targeting consists of (4)

Answer 10

Farnesyl Transferase Inhibitors (FTIs)
CDKIs
Receptor Tyrosine Kinase Inhibitors (RTKIs)
Protein Kinase C Inhibitors (PKCIs)

Question 11

A CDKI which inhibited CDK4 would have the effects of restoring function to ___

Answer 11

p16

Question 12

Receptor Tyrosine Kinase Inhibitors differ from other signal transduction inhibitors such as CDKIs, FTIs how?

Answer 12

They target signal transduction at the level of cell membrane receptors, rather than further downstream.

Question 13

Two FTIs in clinical use

Answer 13

Tipifarnib
Lonafarib

Prevent the post-translational modification and membrane localisation of Ras = block the proliferative signal transduction.

Question 14

What are the most well known examples of Receptor Tyrosine Kinase Inhibitors?

Answer 14

Iressa

Herceptin

Question 15

Glivec inhibits

Answer 15

Both PDGF RTK and the tyrosine kinase associated with the Bcr/Abl fusion protein present in patients with chronic myeloid leukaemia (CML).

Question 16

Protein Kinase C (PKC) is one of the

Answer 16

Most ubiquitous of intracellular signal transduction targets for inhibition.

At least 12 isoforms exist, and these are intimately involved in cell signals leading to proliferation and differentiation.

Question 17

What is the best example of a PKC inhibitor?

Answer 17

Tamoxifen - it is also an oestrogen receptor blocker.

Question 18

Staurosporine is an example of

Answer 18

A PKC inhibitor.

Question 19

mTOR inhibitors may have particular utility in tumours which have lost the function of what tumour suppressor gene?

Answer 19

PTEN loss leads to activation of P13 kinase pathway.