3.6 Downstream receptor targets

Question 1

What are the 2 types of downstream receptor targets?

Answer 1

1. P13K/AKT/MTOR signaling pathway.
2. The RAS-RAF-MEK-ERK pathway, also referred to as the mitogen-activated protein kinase (MAPK) cascade

Question 2

What does the P13K/AKT/MTOR signaling pathway stand for?

Answer 2

Phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR)

Learn the abbreviation only P13k/AKT/MTOR signaling pathway

Question 3

Which 3 kinases feed into the P13k/AKT/MTOR pathway?

Answer 3

1. Epidermal growth factor (EGFR)
2. Human epidermal growth factor (HER2)
3. Platelet derived growth factor (PDGFR)

Question 4

Why is the PK13/AKT/MTOR pathway a target in cancer treatment?

Answer 4

PK13/AKT/MTOR signaling pathway has been found to be disregulated in almost all human cancer types including

• Breast cancer
• Colorectal cancer
• Ovarian cancer and…

Some haematological malignancies.

Question 5

What are 3 ways the PK13/AKT/MTOR signaling pathway can become dysregulated?

Answer 5

The PK13/AKT/MTOR signaling pathway can become dysregulated when there is:

1. A loss or inactivation of the tumour supressor gene PTEN (Phosphatase and Tensin homolog)
2. A mutation or amplification of P13K itself
3. Activation of tyrosine kinase growth factor rceptor on oncogenes upstream from P13K

Question 6

How can drugs influence the PK13/AKT/MTOR pathway?

Answer 6

They inhibit the P13k/AKT/MTOR pathways which can lead to reduced cellular proliferation, tumour progression and apoptosis

Question 7

Which types of drug might effect different parts of the PK13/AKT/MTOR signaling pathway?

Answer 7

everolimus (mTOR inhibitor)
temsirolimus (mTOR inhibitor)
idelalisib (PI3K inhibitor).

Question 8

WHat is the RAS-RAF-MEK-ERK pathway also known as

Answer 8

Mitogen Activated Protein Kinase (MAPK) cascade

Question 9

Growth factors, cytokines and chemokines, hormones

What activates the MAPK pathway?

Answer 9

A number of factors can activate the MAPK signaling pathway including:
Growth factors such as epidermal growth factor can bind to their respective cell surface receptors, leading to the activation of downstream signaling cascades, including the MAPK pathway.

Various cytokines and chemokines, which are small signaling proteins involved in immune responses and inflammation, can activate the MAPK pathway. For example, tumor necrosis factor alpha (TNF-α) and interleukins (ILs) can stimulate MAPK signaling upon binding to their receptors.

Hormones such as adrenaline (epinephrine), insulin, and thyroid-stimulating hormone (TSH) can activate the MAPK pathway through their respective receptors and downstream signaling events

Question 10

How can th MAPK signaling pathway cascade be disrupted?

Answer 10

Inhibit endothelial growth factor (EGFR) or other extracellular growth factors involved in the activation of the MAPK cascade

Question 11

How might the MAPK signaling pathway cascade be influnced in colorectal cancer?

Answer 11

In colorectal cancers with no RAS mutation (e.g. RAS wild type) the EGFR inhibitor Cetuximab may be used.

Question 12

What is the main issue with Endothelial Growth Factor (EGFR) inhibitors such as Cetuximab?

Answer 12

Increasing levels of resistance diminishes the drugs effect over time.

Question 13

What approach is used to overcome this problem of resistance?

Answer 13

Braf inhibitors e.g. Dabrafenib and MEK inhbitors e.g. Trametinib can be used in combination in melanoma to try to delay resistance

Question 14

If the BRAF inhibitors and MEK inhibitors work downstream, are they working inside or outside of th cell?

Answer 14

Inside of the cell

Question 15

On this basis are the drugs which work on this cascade likely to be large or small molecules?

Answer 15

Small

Question 16

Give two example of the drugs used on the MAPK cascade

Answer 16

1. Braf inhibitors e.g. Dabrafenib
2. MEK inhbitors e.g. Trametinib

Question 17

Note to Jamie

Answer 17

Check out the video at the bottom of 3.6.