Drug resistance Flashcards
Describe drug influx/efflux as a mechanism of drug resistance.
- The balance between influx and efflux will determine the intracellular concentration of a drug.
- Most drugs enter cell by passive or facilitated diffusion.
- Some drugs are effluxed by protein transporters actively, e.g. P-glycoprotein which effluxes some lipophilic drugs.
- P-glycoprotein is also known as multi-drug resistant (MDR1) protein and part of the ATP-binding cassette transporters.
- MDR1 is overexpressed in many cancers (intrinsic) or can be induced by chemotherapy (acquired). It is associated with chemotherapy failure and chemoresistance in several cancers as it promotes drug efflux.
- Recent reports have also shown that some SMIs such as Imatinib are substrates for MDR1.
- MDR1 inhibitors have been developed but studies are not yet promising.
Describe inhibition of apoptosis as a mechanism of drug resistance.
- Cancer therapies can be targeted to BCl-2 (such as ABT-737), IAPs.
- Oncogenic mutations during tumorogenesis drive transcription of the above genes and are associated with resistance to several chemotherapies.
- Overexpression of BCl-2 linked to resistance against cytotoxic chemotherapy.
Describe drug inactivation/lack of activation as a mechanism of drug resistance.
– Epigenetic silencing can occur on enzyme which activates the chemotherapeutic drug.
– Overexpression of target will reduce effectiveness of drug.
– Mutations, chromosomal rearrangements can occur on target to prevent drug from binding/attacking it. They are referred to as gatekeeper residue mutations – first mutation for Imatinib was missense causing the drug to no longer bind while it still maintained its catalytic activity.
Second gen SMIs have been developed to work on imatinib resistant tumours – will they also eventually develop resistance?
Describe DNA damage repair as a mechanism of drug resistance.
- DNA damage repair inhibition can be target of therapy, especially since cancer cells tend to rely on one method of DNA repair – causing cancer cell specific death (synthetic lethality). Examples include PARP inhibitors.
- However a few mutant strains of BRCA2 have been able to restore their repair function.
- Defects in mismatch repair system have been linked to resistance to certain chemotherapies such as carboplatin.
- Overexpression of nucleotide excision repair has been linked to resistance to certain platinum based drugs – as NER will allow repair of DNA damage caused by these drugs.
Describe oncogenic bypass as a mechanism of drug resistance.
– Use of alternative signalling pathways.
– This is emerging as a major mechanism of resistance against the newer targeted therapies.
– While the drug target is inhibited, an alternative kinase/signalling molecule is activated allowing the downstream pathway to continue.
E.g. 1. MET is activated from use of EGFR inhibitors and can activate downstream effectors of EGFR signalling.
E.g.2. Vemurafenib – B-raf inhibitor (targets most commonly mutated form) has high clinical response rates but secondary resistance eventually develops.
–This is due to several resistance mechanisms, including activation of alternative Raf isoforms and selection of tumour cells with acquired mutations in pathway allowing it to continue without b-raf.
Describe tumour stem cells as a mechanism of drug resistance.
- Tumour stem cells (or tumour sustaining cells) – there’s evidence that chemotherapy doesn’t kill these sustaining cells, leading to the tumour re-emerging and relapse.
- This is believed to be due to the stem cells having ABC transporters, an active DNA repair system and their resistance to apoptosis (and their limitless replicative potential!).
- Tumour stem cells have been shown to express high levels of the MDR transporters which will actively efflux drugs out of the cell to protect from damage.
- We are now identifying agents that will also target the tumour stem cells – e.g. EZH2, Histone-lysine N-methyltransferase is highly expressed in a number of cancers and is involved in maintaining tumour stem cells.
- Also ABCG2 inhibitors combined with chemotherapy seems very promising.
