lectures Flashcards
Describe EGFR activation of RAS
L1
EGF ligand binds
receptors dimerise
phosphorylation of intracellular tyrosine on the receptor.
Grb2 and SOS bind and then activate Ras (via swapping the GDP for GTP)
Ras has an intrinsic GTPase that normally cleaves the phosphate to turn itself off.
Oncogenic Ras loses this function
What can Ras activate?
L1
Ras can:
Stimulate protein synthesis and transcription (Via Raf MEK Erk1)
Stumlate cell growth, stimulate cell proliferation, and Inhibit apoptosis (Via PI3K Akt )
can even stimulate cell movement.
Causes of increased EGFR (or any growth factor) activity in cancers
L1
Autocrine activity
Mutations in receptor causing ligand independent firing
Overexpression (amplification)
What are exceptional responders?
L1
group of patients who respond well to treatments
eg: asian female non smokers nonsmalll cell lung cancer (with activating point mutation in cytoplasmic tail of EGFR) responded to Gefitinib/Erlotinib
Use of Cetuximab
L1
Standard of care for EGFR positive Colorectal cancer that does not have a Ras mutation.
(sequence ras in all colorectal tumours and if mutated then dont give Cetuximab)
Cetuximab (blocking EGFR) is really effective in someone with wildtype Ras.
No benefit in colon cancer with Ras mutation downstream from receptor.
Causes of loss of antigrowth (anti-replication)
L1
Checkpoints in cell cycle that block progression if Genome is damaged.
Rb controls entry from G1 into S phase.
When hypo phosphorylated it puts a break on cell replication.
Rb is key in whether cells divide.
Rb is abnormal in 80% of cancers.
describe the control of entry into S phase from G1
L1
cyclin D:CDK4 phosphorylate protein Rb
When hypo phosphorylated it puts a break on cell replication.
breaks come off when it is phophorylated
E2F is released, leading to entry into S phase
What drugs can inhibit cell replication? (inhibit insensitivity to antigrowth)
L1
CDK4/6 inhibitors block cell cycle progression
(eg Palbociclib)
they block progress from G1 to S phase
Examples of angiogenisis ACTIVATORS
L1
VEGF
bFGF
examples of angiogenesis inhibitors
L1
Thrombospondin - 1
why do cancers bleed a lot?
L1
the blood vessels grow too quickly and in a disorganised way are poorly supported and fragile
describe anti angiogenesis therapies
L1
Two ways:
Anti-VEGF monoclonal antibodies (Eg: bevacizumab -best known and commonly used)
Small molecules that inhibit VEGF receptor signaling (eg: Cedranib)
Describe limitations of angiogenesis inhibitors in cancer
L1
Don’t have a permanent effect once the drug is stopped eg after a year or two of treatment
What do telomeres do?
L1
they protect the ends of chromosomes from being treated like broken DNA
Act as a molecular clock
once they shorten a certain amount the cells undergo sensecence.
What is telomerase
L1
It is a reverse transcriptase that extends telomeres using RNA as a template.
Immortalises the cancer cells as they dont know when to stop
gives them similar ability as stem cells and embryonic cells
mechanisms leading to apoptosis
L1
Extrinsic pathway
Exectional Caspases (3, 6, 7) cleave cellular proteins and cell dies.
Describe the extrinsic pathway of cell death
L1
Responds to external cell signals. Death ligands (eg: FasL or TNF) activate caspase 8
Activated caspase 8 then activates Exectional Caspases (3, 6, 7) cleave cellular proteins and cell dies.
Describe the intrinsic pathway
L1
DNA damage and p53 activation, drugs, cell cycle abnormalities all influence the release of ctochrome - C from the mitochondria.
cytochrome-C then forms an apoptosome and activates Caspase-9
Caspase 9 then activates Exectional Caspases (3, 6, 7) cleave cellular proteins and cell dies.
What is Bid? (in apoptosis signaling)
L1
links activation of the extrinsic pathway(eg FasL) to intrinsic pathway (activating mitochondria)
What does Bcl2 do
(and a drug that inhibits this)
L1
pro survival (anti-apoptotic)
inhibits/regulates release of cytochrome c from mitochindria
Venetoclax - small molecule inhibitor, blocking Bcl2
(what does PTEN do)
L1
it is a tumour suppressor that inhibits AKT.
This results in more Bad (proapoptotic) that stimulates cytochrome- C release.
(as AKT inhibits Bad)
what are the 3 phases leading to avoiding immune destruction
L1 RM
Elimination, Equilibrium, Escape.
Eliminate - recognises cancer and destroys it
Equilibrium - cancer learns hw to bypass the immune system or the immune system “forgets” that the cancer is foreign.
Escape - Stops killing the cancer, can grow unchecked.
What is the immunoediting hypothesis in cancer development?
L1 RM
basically that we all develop cancer all the time but the immune system gets rid of almost all of them.
many mutations seen in apparently normal skin, but the cancer is actually very rare as the bodies immune system is mopping it up
(Martincorena et al, 2015)
how can cancer cells inhibit T cells?
and name a treatment targeting this
L1 RM
Have abnormalities in PD-1 and CTLA 4 (costimulation along with MHC) signaling to T cells
Nivolumab (in melanoma) - binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, releasing PD-1 pathway-mediated inhibition of the immune response, including the anti-tumor immune response