L16 - TYROSINE PHOSPHORYLATION & DISEASE Flashcards
FGFR3 mutation
receptor key in long bone growth
*mutations occur that activate the early differentiation of proliferative chondroblasts into non-proliferative chodrocytes leading to no bone growth
what are Gain of function mutations
autosomal dominant mutations with a graded severity that require only one mutated allele
examples of gain of function mutations in FGFR receptors
achondroplasia (commonest) - G380R mutation in the membrane spanning domain –> causes dimerisation in the absence if ligand binding
hypochondroplasia - N540K mutation at TK1 domain
coronal craniosynostosis - P250R at extracellular domain (IG2-IG3) –> causes the early sealing of skull plates causing the brain to move sideways
Cancer hallmarks
uncontrolled proliferation, growth supressor evasion, resisting apoptosis, immortality, angiogenesis, invasion and metastasis, evasion of immune response
how do RTKs relate to cancer
RTKs are key in
*cell proliferation
*Growth suppression evasion
* Angiogenesis
* Invasion and metastasis
* Immune evasion
4 cancer initiating factors
- Infections
- Carcinogens
- UV radiation
- others
how many cancers are initiated by viruses
10-20%
list the 4 main oncoviruses
*Epstein Barr virus (EBV)
*human papilloma virus
*hepatitis B and C
what does EBV cause
Burkitt’s lymphoma and other B cell lymphomas
what does HPV cause
cervical cancer and head & neck squamous cell carcinoma (HNSCC)
what kind of cancer do hep b & c
hepatocellular carcinoma (liver cancer)
5 underlying mechanisms of tyrosine-kinase based cancer pathogenesis
- viral hijacking
- Ligand: autocrine production of ligand
- chromosomal translocation: oncogenic fusion of proteins
- Gene amplification: RTKs dimerise in the absence of ligand
- Activating/gain of function (GOF) mutation
TRUE or FALSE: RTKs cause one type of cancer
false- one RTK can be responsible for the proliferation of many different types of cancer
dysregulated EGFR signalling
- Viral oncogene “highjacking” of HER signalling
- Excess HER ligand → over-expression/autocrine (EGF, TGFα)
- Gene amplification → EGFR/HER1 or HER2 overexpression
- Activating mutation in HER genes (e.g. EGFRvIII)
most common EGFR dysregulations
gene amplification and activating mutations
lung cancer pathway vs brain cancer
EGFR mutation causes lung cancer whereas brain cancer has an overexpression/ over amplification of EGFR
both mutations activate MAPK, PI3K and STAT3 pathways
breast cancer
HER2 genes are overexpressed in HER2 driven breast cancer causing up to 50 copies of the gene being transcribed allowing for homodimerization and constitutive activation
occurs in ~20% of breast cancers
Gastro-Intestinal Stromal Tumour (GIST)
Caused by activating mutations in c-KIT (80%) or 20% PDGFRα mutations
VEGFR Signalling and cancer
- Hypoxia induces VEGF secretion
- Most tumour cells secrete VEGF-A
- VEGF-A signals via VEGFR2 in
tumour angiogenesis
3 VEGF receptors
- VEGFR1 & 2 - mainly vascular
- VEGFR3 - mainly lymphatic
chronic myeloid leukemia
translocation joins c-Abl (chr 9) & breakpoint cluster region gene (BCR) (chr 22) to create a constitutively active fusion protein, BCR-abl
this mutation occurs in all CML - moleculary homogenous
Targeted therapies for cancer
target oncogene-driven Tk signalling
*humanised antibodies- large molecules that function extracellularly (-abs)
*small molecule inhibitors - membrane
permeable & target kinase domains
(-ibs)
Timeline of targeted RTK therapies
1980s - developed non-specific TK inhibitor staurosporine
1990s- developed specific, individual TKs known to be activated by GoF
mutation or over-expression in human cancers were targeted for drug development
2000s - imatinib is developed for BCR-abl mutation for CML + Trastuzumab - humanised antibody against ECD of
HER2/ErbB2 (BC)
Imatinib
binds in the ATP cleft and prevents kinase phosphorylation shutting of the abl kinase and inducing apoptosis
also inhibits c-Kit + PDGFRα (GIST)
