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
