Notesale: Turn your study into money

Document Preview

Extracts from the notes are below, to see the PDF you'll receive please use the links above

---

RECEPTOR TYROSINE KINASES: THERAPEUTIC TARGETS FOR CANCER

Introduction to RTKs:
1
...
Burn
...
– these are the conventional treatments for cancer today
...
Cut – surgical removal of the cancer cells
...
Burn – radiotherapy to remove the disease parts
...
Poison – chemotherapy (medication)
...
However, these are not effective for all types of cancer and also have some harmful
side effects
...
Mapping of the human genome helped in the understanding and use of drugs that
are more specific to the patient (personalised medicine) and to the type of cancer
(i
...
use of antibodies)
...
Cancer is a disease of uncontrolled cellular proliferation
...
Normal cells receive growth factor signalling, which signals to the cell to begin
proliferation, and additional signalling to stop proliferation
...

3
...

4
...
e
...

5
...












6
...

7
...

8
...




-

Within their inactive form, receptor tyrosine kinases are present as monomers
...

These phosphorylated residues become the docking sites for the Grb2 (SH2 and
SH3 domain-containing protein)
...
Aberrant function of the RTK in cancer is often due to mutations that lead to the
resistance of RTK inhibitors, and this is especially seen in the ABL family:
- Overexpression is a common mechanism
- Truncation/gene mutation – leads to conformational changes of the receptors,
without the presence of the ligand
...
Gleevec [Imatinib] is a RTK inhibitor that targets mutations – more specifically, the
bcr-abl translocation (t(9:22) – resulting in formation of the Philadelphia
chromosome (chromosome 22)) that leads to the development of chronic myeloid
leukaemia (CML), which is a liquid tumour
...
The BCR-ABL mutation expresses a fusion oncoprotein with tyrosine kinase activity
...
e
...

Currently, CML patients treated with the drug have normal life expectancy
...


Small molecule inhibitors:
1
...


-





Due to oncogenic addiction (where the tumours are dependent on a specific
oncogenic pathway for survival and proliferation despite a plethora of genetic
alterations), this treatment is very successful
...
Kit and Abl inhibitor – imatinib
3
...

4
...

•

Monoclonal Antibodies:
1
...
VEGF – bevacizumab (Avastin)
3
...
These antibodies target the extracellular domains of the receptor, thus
preventing the ligands from binding – however, they would obviously be
ineffective against oncogenic transformations that leave receptors ligandindependent
...
EGFR/HER1 and HER4 have many ligands – lack specificity, whereas HER2 and HER3
are more complicated receptors
...
In that, HER2 lacks a ligand binding domain and HER3 lacks a kinase domain –
therefore, when these two receptors undergo heterodimerization with each other,
they are able to fully function and lead to the downstream signalling cascade
...
EGFR overexpression is very common in epithelial tumours, especially head and neck
cancers, renal cell cancer, non-small-cell lung cancer, and other types of solid
tumours
...
Therefore, finding an effective therapy against this receptor and its ligands would be
very effective
...
Cetuximab is a human/mouse chimeric monoclonal antibody for treatment of
metastatic colorectal cancer and head and neck cancer
...
This antibody binds specifically to the extracellular domain of EGFR but toxicities
include:
- Infusion reaction
- Pulmonary toxicity
- Skin toxicity
5
...

6
...
e
...

7
...

8
...

9
...

10
...

11
...

12
...

13
...

14
...

- Met gene amplification



HER2 INHIBITION:
1
...






2
...

3
...

4
...

5
...

6
...

• Herceptin proposed mechanisms of action:
1
...
Herceptin blocks this cleavage
...
Antibody-induced downregulation due to internalization and degradation thereby
inhibiting receptor dimerization (including heterodimerization with other EGFR
family members), and thus inhibition of signalling
...
Induction of antibody-dependent cellular cytotoxicity (ADCC):
- For Herceptin this is probably not the main mode of action as it is not optimised
for ADCC
...
e
...

4
...



OVERALL: Cancers such as lung, melanoma and head and neck cancer have very high
mutation rates
...




MECHANISM OF RESISTANCE:
- A: Cancer stem cells are heterogenous cells that can give rise to multiple cell
types, thus increasing the chances of metastasis
...

- B: secondary mutations change the environment of the cancer cells thus allowing
the cells to escape cell death
...
Tumours can resist RTK inhibitors because the initial target of the therapies is not
critical to survival of those tumour cells – primary resistance
...
The tumour can also circumvent the inhibited pathway by activation of other
pathways
...
Furthermore, the therapies may only partially inhibit the receptors because the
inhibitor itself is not potent enough or perhaps, secondary mutations could prevent
the inhibitor binding to the receptor
...

4
...

5

---