Drug Resistance Flashcards
What are common resistance mechanisms?
Decreased drug influx Increased efflux Activation of DNA repair Blocked apoptosis Activation of detoxification systems (Cytochrome P450)
What is inherent resistance?
Pre-existing before drug exposure
What is adaptive resistance?
Chemotherapy-induced selection pressure
What percentage of people have inherent resistance?
10-20%
Name some non-mutation related resistance mechanisms
Downregulation of the immune response in resistant melanoma (reduction in CD8+ T cells and altered antigen expression)
Methylation changes
Pathway rewiring
Metabolic switch - Glucose-glutamine metabolism
What can be used as a surrogate for humans when investigating mutations which induce resistance?
Patient derived xenografts
Give an example of a PARP inhibitor used for breast and ovarian cancers with BRCA1/2 mutations?
Olaparib
How does resistance to Olaparib occur?
The cancer cells restore their BRCA1/2 mutation so they can no undergo HR
Which melanoma patients tend to have inherent resistance to anti-PD-1 therapies?
Those who have a low mutational burden due to low numbers of neoantigens
When are ovarian cancer patients typically diagnosed?
FIGO Stage III/IV
What is the best form of treatment for ovarian cancer?
Surgery, typically with neo-adjuvant chemotherapy
What is the first line chemotherapy treatment for ovarian cancer?
Carboplatin +/- Paclitaxel
What is the main issue with ovarian cancer in terms of surgery?
They are often too far along for surgery to be effective
What is a good biomarker or platinum drugs?
Glutathione-S-Transferase P1 (GSTP1) - high levels suggest sensitivity
Why can gene mutation not be measured as a biomarker for ovarian cancer?
It is hardly ever mutation, main mutation is p53 which is too common along different cancers to be used as a biomarker
Instead of using mutation expression for ovarian cancer, what is used as a marker?
mRNA expression
What do ovarian cancer patients produce?
Ascites in the abdomen
What is ascites rich in?
Cancer cells
When does ascites start to be made?
when they are starting to become drug resistant but aren’t yet
What can ascites be used for?
Grown in culture to investigate resistance mechanisms
What has ascites experiments known?
That when resistance occurs, FGF1 is upregulated and so is its receptor FGFR2
What do drug resistant ovarian cancer cells look like?
Long and spindly
What do drug sensitive ovarian cancer cells look like?
Small and round
Why do ovarian drug resistant cancer cells adapt this morphology?
They are undergoing a epithelial-mesenchymal transition
What is FGF1s role in EMT switch?
They make genes which make the TFs needed for EMT
Name a drug which inhibits FGFR activation
Suramin
What signalling pathways does FGFR stimulate?
AKT
MAPK
CaMK
Name an ovarian cell line which is currently used
A2780
what is the issue with A2780 cells?
They are given different platinated drugs now to what they were originally
Given drug doses which would not be used in clinics
They’ve been grown in culture for a very long time
What is MDR1?
A multi-drug resistance gene
produces an efflux pump
What does the MDR1 pump cause?
As soon as a drug comes into the cell via passive diffusion, it encounters the drug transporter in the cell membrane and is actively pumped back out
What are good drug substrates of MDR1?
Paclitaxel
Doxorubicin
Olaparib
What are bad drug substrates of MDR1?
Platinum drugs
In MDR1 expressed cells, what is there an abundance of at the cell surface?
P-glycoprotein
What drugs can be used to target Palitaxel and Olaparib resistant cells?
P-glycoprotein inhibitors, verapamil and elacridar
What can you use to measure MDR1 levels and why?
Calcein
Calcein is cleaved by MRD1 and therefore cancer cells will have decreased expression of Calcein
What signalling pathway can be targetted in ovarian resistant cells and whats the drug
AKT
MK-2206 AKT inhibitor
