1. Lung Cancer Tumour Markers

2. The origin of cancer What is cancer?
Cancer Research UK defines it as: “… when abnormal cells divide in an uncontrolled way.

3. The Cell Cycle

4. The Cell Cycle Go is modulated by:
Mitogens, stimulate cell division, mostly by removing intracellular negative feedback controls that block progress through the cell cycle.
Growth factors, which stimulate cell growth by promoting the synthesis of proteins and other macromolecules and by inhibiting their degradation.
Survival factors, which promote cell survival by suppressing apoptosis.
Resting phase or cell quiescence (heart/neuron)

5. ALK -1 EGFR KRAS These are tyrosine kinases The Cell Cycle
Go is modulated by:
ALK -1
EGFR
KRAS
These are tyrosine kinases

6. Al Pacino says: Most receptors for growth factors are tyrosine kinases
Regulation of The Cell Cycle
Most receptors for growth factors are tyrosine kinases
A tyrosine kinase?
WHAT THE &%$* IS A TYROSINE KINASE ?!
Al Pacino says:

7. Most receptors for growth factors are tyrosine kinases
Regulation of The Cell Cycle
Most receptors for growth factors are tyrosine kinases
Discovered in 1982
Receptor for epidermal growth factor (EGF)
When activated, transfers a phosphate group from ATP to selected intracellular tyrosine side chains.
These phosphorylated domains are recognised by intracellular proteins and start a signal cascade.
Phase 1: Extracellular signal
Phase 2: Intracellular signal cascade
Phase 3: Profit.

8. EGFR: Epidermal Growth Factor Receptor
Involved in growth; cell proliferation; differentiation and survival
Family of four tyrosine kinase receptors
HER-1 (ErbB-1)
HER-2/neu (ErbB-2)
HER-3 (ErbB-3)
HER-4 (ErbB-4)

9. EGFR: Epidermal Growth Factor Receptor
A transmembrane cell signalling receptor with four distinct domains:
Tyr
EGF binding site
Plasma membrane
Tyrosine kinase
Cytoplasmic tail

10. EGFR: Epidermal Growth Factor Receptor
How does it function?
EGF
EGF
Tyr
Epidermal growth factor (EGF) binds to its receptor (EGFR) on the cell membrane

11. EGFR: Epidermal Growth Factor Receptor
How does it function?
Homo- and hetero-dimerization of the transmembrane region and autophosphorylation of tyrosine kinase molecules.
Signal cascade pathway activated (e.g.MAPK) leading to DNA synthesis and cell replication
Tyr
EGF P
ATP
ADP

12. EGFR: Epidermal Growth Factor Receptor
RAS
GDP
MYC
Transcription
Grb
RAS
GTP
RAS
GTP
SOS
MEK
RAF
MNK
CREB
MAPKKK
ATP
ADP
ATP
ADP
MAPKK
MAPK

13. All this preparation is ignored
Kirsten rat sarcoma viral oncogene homolog
KRAS = Kirsten rat sarcoma viral oncogene homolog
KRAS is a molecular switch.
KRAS recruits and activates the proteins required in growth factor receptors, e.g.: B-RAF (a member of the MAPK pathway)
All this preparation is ignored
BRAF initiates the whole signalling cascade at this point
Also known to play a role in the Warburg effect of malignant tumours.
BRAF was here..

14. ALK-1: Anaplastic lymphoma kinase
Adenocarcinoma of the lung responsible for 3-5% of non-small cell lung cancer
ALK-1 is:
the result of a inversion fusion gene mutation on 2q
ALK and EML1 change position
ALK fuses to EML4
Produces a chimeric fusion protein with constitutive ALK1 action.
Promotes and maintains malignant behaviour.
Almost mutually exclusive with EGFR or KRAS

15. TYROSINE KINASE TAKE HOME MESSAGE
Cell signalling is a complicated process involving many interlocking parts
One solitary change can upset the whole cascade.
Molecular biology is never as simple as it appears!