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Cancer Pharmacology > Drug Resistance > Flashcards

Drug Resistance Flashcards

1
Q

What are common resistance mechanisms?

A 
Decreased drug influx 
Increased efflux
Activation of DNA repair 
Blocked apoptosis 
Activation of detoxification systems (Cytochrome P450)
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2
Q

What is inherent resistance?

A

Pre-existing before drug exposure

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3
Q

What is adaptive resistance?

A

Chemotherapy-induced selection pressure

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4
Q

What percentage of people have inherent resistance?

A

10-20%

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5
Q

Name some non-mutation related resistance mechanisms

A

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

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6
Q

What can be used as a surrogate for humans when investigating mutations which induce resistance?

A

Patient derived xenografts

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7
Q

Give an example of a PARP inhibitor used for breast and ovarian cancers with BRCA1/2 mutations?

A

Olaparib

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8
Q

How does resistance to Olaparib occur?

A

The cancer cells restore their BRCA1/2 mutation so they can no undergo HR

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9
Q

Which melanoma patients tend to have inherent resistance to anti-PD-1 therapies?

A

Those who have a low mutational burden due to low numbers of neoantigens

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10
Q

When are ovarian cancer patients typically diagnosed?

A

FIGO Stage III/IV

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11
Q

What is the best form of treatment for ovarian cancer?

A

Surgery, typically with neo-adjuvant chemotherapy

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12
Q

What is the first line chemotherapy treatment for ovarian cancer?

A

Carboplatin +/- Paclitaxel

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13
Q

What is the main issue with ovarian cancer in terms of surgery?

A

They are often too far along for surgery to be effective

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14
Q

What is a good biomarker or platinum drugs?

A

Glutathione-S-Transferase P1 (GSTP1) - high levels suggest sensitivity

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15
Q

Why can gene mutation not be measured as a biomarker for ovarian cancer?

A

It is hardly ever mutation, main mutation is p53 which is too common along different cancers to be used as a biomarker

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16
Q

Instead of using mutation expression for ovarian cancer, what is used as a marker?

A

mRNA expression

17
Q

What do ovarian cancer patients produce?

A

Ascites in the abdomen

18
Q

What is ascites rich in?

A

Cancer cells

19
Q

When does ascites start to be made?

A

when they are starting to become drug resistant but aren’t yet

20
Q

What can ascites be used for?

A

Grown in culture to investigate resistance mechanisms

21
Q

What has ascites experiments known?

A

That when resistance occurs, FGF1 is upregulated and so is its receptor FGFR2

22
Q

What do drug resistant ovarian cancer cells look like?

A

Long and spindly

23
Q

What do drug sensitive ovarian cancer cells look like?

A

Small and round

24
Q

Why do ovarian drug resistant cancer cells adapt this morphology?

A

They are undergoing a epithelial-mesenchymal transition

25
Q

What is FGF1s role in EMT switch?

A

They make genes which make the TFs needed for EMT

26
Q

Name a drug which inhibits FGFR activation

A

Suramin

27
Q

What signalling pathways does FGFR stimulate?

A

AKT
MAPK
CaMK

28
Q

Name an ovarian cell line which is currently used

A

A2780

29
Q

what is the issue with A2780 cells?

A

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

30
Q

What is MDR1?

A

A multi-drug resistance gene

produces an efflux pump

31
Q

What does the MDR1 pump cause?

A

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

32
Q

What are good drug substrates of MDR1?

A

Paclitaxel
Doxorubicin
Olaparib

33
Q

What are bad drug substrates of MDR1?

A

Platinum drugs

34
Q

In MDR1 expressed cells, what is there an abundance of at the cell surface?

A

P-glycoprotein

35
Q

What drugs can be used to target Palitaxel and Olaparib resistant cells?

A

P-glycoprotein inhibitors, verapamil and elacridar

36
Q

What can you use to measure MDR1 levels and why?

A

Calcein

Calcein is cleaved by MRD1 and therefore cancer cells will have decreased expression of Calcein

37
Q

What signalling pathway can be targetted in ovarian resistant cells and whats the drug

A

AKT

MK-2206 AKT inhibitor

Cancer Pharmacology (13 decks)

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