signalling

Question 1

main routes of oncogenic RTK activation

Answer 1

• amplification - genomic over expression
• overexpression - transcriptional upregulation
• loss of inhibitory domains
• mutations in key residues

overexpression can lead to hyperactivation = hard to turn off

Question 2

autocrine signalling

Answer 2

where mutant RAS or oncogenes can lead to the expression of ligands and then these ligands can be secreted and activate receptors on the cell themselves.

Question 3

possible routes of treatment

Answer 3

• use monoclonal antibodies to block ligand binding
• use mAbs to stop receptor dimerising
• use drugs that inhibit the kinase activity
• monotherapy of TKI of mAb against RTK have good responses

Question 4

targeting RTKs

Answer 4

• EGFR has multiple ligands
• has mAbs to block the receptor dimerising
• has variant specific inhibitors
• some are mutant specific Osimertinib T790M

Question 5

Progression free vs overall survival

Answer 5

• progression free survival measures the length of time after receiving a treatment, where the disease does not progress
• this can be recorded much earlier than overall survival
• overall survival measures the time between recieving therapy and succumbing to illness
• this measures later but has more factors at play

Question 6

how do monotherapies downstream of RAS work

Answer 6

• BRAFV600E has good initial response to mutant specific therapies
• same is true for MEK inhibitor monotherapies such as trametinib
• PI3/AKT inhibition has had less success
• relapse after prolonged treatment is very common