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[ONCG2004] Lung, Breast, And Prostate Cancer > 2. Growth Factor & GFRs > Flashcards

2. Growth Factor & GFRs Flashcards

1
Q

List a few type of cells that may be present in the tumour cell micro environment

A
  • Fibroblasts
  • Cancer cells
  • Macrophages (TAM)
  • Endothelial (blood vasculature)
  • T cells (immune cells)
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2
Q

What are the 4 types of growth factors?

A
  • Receptor tyrosine kinases (RTKs)
  • Receptor Serine-Threonine kinases
  • Trans-membrane domain receptors
  • G protein coupled receptors
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3
Q

What types of GFs do NOT act by phosphorylation

A

Trans-membrane domain receptors & G-protein coupled receptors

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4
Q

What are 3 examples of receptor tyrosine kinases and their respective ligands?

A

ErbB/HER1 : EGF
Flt/KDR : VEGF
cMet : HGF

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5
Q

What are 2 examples of serine-threonine receptor kinases and their respective ligands?

A

Smad : TGF-b
ALK1-7 (Activin-like kinase) : BMP

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6
Q

What is the difference between ALK1-7 and ALK?

A

ALK1-7 : Activin-Like Receptor, it is a serine-threonine kinase
ALK: Anaplastic lymphoma kinase (a receptor tyrosine kinase)

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7
Q

What is an example of a G-coupled receptor and its ligand?

A

Frizzled : Wnt

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8
Q

What types of cancer/process are driven by the RTK-mediated growth factors:
- EGF
- VEGF-A
- VEGF-C
- HGF
- FGF1
- PDGFA/B

A
  • EGF: breast & lung cancer
  • VEGF-A: angiogenesis -> tumour growth
  • VEGF-C: lymphangiogenesis -> metastasis
  • HGF: liver metastasis
  • FGF1: bile duct cancer
  • PDGFA/B: sarcoma, GI stromal tumours (GIST)
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9
Q

What are the RTKs associated with these cancers/processes?
- breast & lung cancer
- sarcoma & GI stromal tumours
- angiogenesis
- bile duct cancer
- lymphangiogenesis

A
  • breast & lung cancer: ErbB1-4 (EGFR, HER2-4)
  • sarcoma & GI stromal tumours: PDGFRA/B
  • angiogenesis: VEGFR2, KDR
  • bile duct cancer: FGFR1
  • lymphangiogenesis: Flt4
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10
Q

What is the GF and the GFR associated with acute myeloid leukemia?

A

GF: granulocyte colony stimulating factor (GCSF)
GFR: CD114

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11
Q

Fill in the blanks:
____, an EGFR used for NSCLC had an ____ in median survival in patients with stage IV cancer who had failed chemo

A

1) Erlotinib
2) increase

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12
Q

Describe the structure of a receptor tyrosine kinase

A

The extracellular domain is made up of leucine-rich repeats and cysteine domains.

The transmembrane domain (TMD) exists between the intra- and extracellular regions

The juxtamembrane connects the TMD to the tyrosine (symbol = Y) kinase domain.

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13
Q

Fill in the blanks:
Receptor Tyosine Kinases signal through _____ _____.
Phosphorylated ____ are recognised by ____ ____ domains in proteins.
Adaptor proteins like ____ have SH2 and SH3 domains.
SH3 domains recognise ____ rich regions in ____ proteins (____)
____-____ase converts GTP->GDP
____ causes Ras to release GDP

A

1) tyrosine phosphorylation
2) tyrosines
3) Src homology2 (SH2)
4) Grb2
5) proline
6) adaptor
7) Son of Sevenless (SOS)
8) Ras-GTP
9) SOS

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14
Q

Describe an overview of the EGFR signalling:

A
  • Ligand (EGF) binds
  • Induces conformational change in EGFR -> homo/hetero dimerisation.
  • Monomer phosphorylates tyrosine residues on cytoplasmic tail of other monomer.
  • TyrP docks adaptor proteins, including Grb2, SHC, which facilitate assembly of signalling complexes
  • Recruitmentment of SOS activates Ras-GTPase -> MAPK pathway -> TF activation
  • Activation of P13K/Akt pathway -> TF activation
  • degradation of EGFR/ induction of inhibitors (PTEN) to regulate EGFR signalling.
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15
Q

Describe the function of Grb2 and its domains

A
  • Grb2: Grabs phosphorylated tyrosine kinases and forms link
    Domains: Src Homology (SH) 2&3
  • SH2: binds to +PY
  • SH3: binds to other proteins (eg SOS) that form signalling complex
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16
Q

How does the structure of Grb2’s domains result in an amplified signal?

A

The ratio of SH2 :SH3 is 1:2, meaning the SH3 can bind 2 adaptor proteins for every 1 phosphorylated tyrosine that SH2 binds

17
Q

Describe the function of the SOS guanine exchange factor in EGFR signalling

A

SOS binds through proline rich domains to Grb2 to initiate signalling complex.
SOS recruits RasGTPase
converts GTP->GDP, initiates downstream signalling eg Ras > Raf (MAPK pathway)

18
Q

What is the downstream transcription factor of the MAPK pathway

A

C-Myc

19
Q

Outline the P13/Akt signalling pathway from EGFR

A

EGFR dimerisation
SHC adaptor proteins
Kinases: Src > P13K > AKT (> Cyclin D, indirect)
-> BAD (adaptor) & casp9 (protease) -> survival of cell

20
Q

In what ways are the VEGFR and EGFR pathways:
- similar
- different

A

Similar:
- Activates MAPK and P13/AKT pathways
- Results in survival & prliferation of cell
Different:
- VEGFR activates PKC pathway
- EGFR = RTK, VEGFR = IgG

21
Q

How can GF pathways be hijacked in cancer?

A
  1. Excess GFR expression
  2. Excess GF signalling
  3. Excess GF production
22
Q

What regions of a gene may be mutated when GFs are over-expressed?

A

Enhancer or Promoter regions

23
Q

Why does over-expression of GFs cause enhanced signalling?

A

GFRs work by dimerisation
Increase expression leads to ligand-index dent activation
(increase probability of dimerising & interacting regardless of ligand presence)
Drives GFR signalling

24
Q

Why is HER2 a good target when EGFR signalling is over-expressed?

A

HER2 can homodimerise and heterodimerise (with EGFR4,3,1) drives expression, and means other GFRs do not need ligand

25
Q

How can gene amplification cause over-expression of GFR genes?

A
  1. Duplication on other chromosomes during mitosis
  2. Duplication on same chromosome during DNA replication
    -> multiple of copies of GFR gene increase expression of protein
26
Q

How many homologous recombination drive over-expression of gene?

A

Swap DNA with partner chromosome
If incorrect,a GFR domain can be inserted into a promoter, causing constitutively active GF domain.

27
Q

What do ‘mab’ and ‘ib’ stand for and what are their features

A

Mab - monoclonal antibody, cannot cross membrane, act intracellularly.
Ib - small molecule inhibitors, usually tyrosine kinase

28
Q

Why does binding the GF extracellularly not wok in cancer treatment?

A
  • if cancer is upregulated/disrupted intracellularly, targeting extracellular GF may have no effect
    (Eg ligand-indeed ent dimerisation of GFRs)
29
Q

What are examples of drugs that inhibit GFR:
- activation
- dimerisation

A
  • activation: cetuximab, panitumumab, nectimumab
  • dimerisation: trastuzumab, pertuzumab
30
Q

What are some examples of drugs that inhibit:
- EGFR
- HER2
- FGFR

A
  • EGFR: erlotinib, gefitinib, osimertinib, dacomitinib
  • HER2: afatinib, lapatinib
  • FGFR: pemigatinib
31
Q

List the way some drugs that target GFRs work

A
  • inhibiting GFR activation
  • inhibiting GFR dimerisation
  • inhibiting GFR translocation
32
Q

What are 3 drugs that inhibit different parts of the MAPK signalling pathway

A

Raf: Vemurafenib
Mek: Trabetinib
ERK: Ulixertinib

33
Q

What factors may affect what part of the signalling process (EG MAPK) you chose to inhibit when making a drug?

A
  • The further from the source (eg from RAS) the more side effects the drug has (eg MEKi have many pathways altered so many side effects)
  • Kinases (eg Raf, mek erk) are easier to block than GEFs/TFs (eg c-Myc, RAS)
34
Q

Finish the sentence:
Growth factor receptors can drive cancer is they are ………

A

Mutated or over-expressed

[ONCG2004] Lung, Breast, And Prostate Cancer (8 decks)

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