CBIO9: Cancer resistance, biomarkers and personalised treatment Flashcards
What is synthetic lethality?
Two hit mutation, where the first hit mutates again to cancel the effect of the second hit
Give an example of synthetic lethality
- Both BRCA1/BRCA2 altered and PARP inhibited
- Secondary mutation in BRCA1/BRCA2 leading to resistance to PARP inhibition
When does cancer therapeutic resistance occur?
when cancers develop resistance to treatments such as chemotherapy, radiotherapy and targeted therapies, through various mechanisms
How can cancer therapeutic resistance occur?
pecific genetic and epigenetic changes in the cancer cell(s) and/or the microenvironment in which the cancer cells reside
What does tumour microenvironment include?
The tumour microenvironment includes non-cancerous cells within and adjacent to the tumour, and the proteins expressed by them that contribute to tumour growth.
For example, increased matrix stiffness of hepatocellular carcinoma cells promotes resistance to chemotherapy.
How can you overcome therapeutic resistance in cancer? (4)
1) Using an alternative drug that works via different mechanisms.
2) Understanding exactly how drug resistance develops in cancer. This allows for the possibility of designing drugs to specifically target it.
3) Applying a combination of therapies to target different aspects of the tumour. This reduces the opportunities for the tumour to become resistant.
4) By personalising treatment. Choosing a treatment that is tailored to a specific patient significantly reduces rates of therapeutic resistance.
How many cases of chemotherapy failure are related to drug resistance?
90%
What are the two types of drug resistance?
Intrinsic
Acquired
What does intrinsic resistance relate to?
Drug resistance mechanism exists prior to treatment: tumours insensitive to chemotherapy are intrinsically resistant
What does acquired resistance related to?
Induced (selected for) by drug treatment: tumours that are mostly sensitive to chemotherapy will be significantly reduced, leaving few cells which may lead to acquired resistance
How is cell death induced following drug treatment (flow scheme basic)
- absorption
- distribution
–> drug influx
(drug activation [- drug inactivation/alterations in drug target) ->
(cellular damage [-adaptive responses/dysfunctional apoptosis) - -> drug efflux
- metabolism
- elimination
How can the anticancer activity of a drug can be limited?
- Poor drug influx or excessive efflux
- drug inactivation or lack of activation
- alterations such as changes in expression levels of the drug target
- activation of adaptive pro-survival responses
- lack of cell death induction due to dysfunctional apoptosis, which is a hallmark of cancer
Give 3 examples of how drug resistance can arise from decreased uptake of drug
1) Methotrexate (toxic folate analogue) resistance commonly occurs by mutation of one or both of the folate transporters. Folate is a vitamin that enters cells using the folate transporters found on cellular membranes. The anti-cancer drug methotrexate is a toxic folate analogue and also uses the folate transporters to enter cancer cells.
2) Resistance to nucleoside analogues (anti-cancer drugs that are similar to nucleotides) has been described as a result of mutation of specific nucleoside transporters.
3) Reduction in plasma membrane receptors and transporters and reduced endocytosis have been shown to occur in cisplatin-resistant cell lines that are resistant to the chemotherapy drug cisplatin.
Explain and give an example of drug resistance due to increased drug efflux
P-glycoprotein (Pgp), also known as MDR1 (multi-drug resistance protein 1), is an ATP binding protein pump in the cell membrane that pumps many foreign substances out of cells. Its over-expression is associated with drug resistance to Pgp substrates e.g. the chemotherapeutic drugs Doxorubicin, taxanes and vinca alkaloids.
Inhibition of Pgp with verapamil, for example, can reverse drug resistance in vitro. The clinical significance of MDR1 over-expression is disputed. There is good evidence to suggest that over-expression of this protein plays a significant role in drug resistance in cases of acute myeloid leukaemia and myeloma, but its role in drug resistance where solid tumours are concerned remains unclear.
Drug resistance can be due to altered drug metabolism to increase detoxification, which means the cancer drugs are no longer toxic. Give 3 examples.
Glutathione (GSH) is a powerful anti-oxidant that protects the cells against the damaging effects of reactive oxygen species. GSH conjugates to platinum chemotherapy drugs (e.g. oxaliplatin and cisplatin) and modifies them to substrates for ABC transporters, which facilitate drug efflux.
CYP450, an enzyme found in the liver, can inactivate irinotecan (Topoisomerase I inhibitor, used in colon cancer).
Metallothionein (MT), a protein found on the membrane of Golgi apparatus, also binds platinum drugs and inactivates them.
Drug resistance can be due to altered drug metabolism to decrease activation, which means cancer drugs are not activated within cancer cells. Give an example.
Cytarabine (also known as AraC), a nucleoside analogue widely used for the treatment of acute myeloid leukaemia (AML), requires phosphorylation to be activated by the enzyme deoxycytidine kinase. Resistance to cytarabine develops when levels of deoxycytidine kinase are reduced, through downregulation or mutation.
alterations of th drug target, such as mutations or altered expression levels, can promote development of drug resistance. Give an example.
Gleevec is an anti-cancer drug that targets the BCR/ABL protein in chronic myeloid leukaemia. Drug resistance develops as a result of mutations occurring at the binding site of the drug within the BCR/ABL protein.
Drug resistance can be due to changes in cellular pathways such as DNA repair pathways. Give an example.
Resistance to the DNA damage-inducing drug cisplatin occurs due to enhancement in DNA repair mechanisms. This can be due to high expression of important components such as ERCC1, an important factor in the NER (nucleotide excision repair) DNA repair pathway.
Drug resistance can be due to changes that result in evasion of apoptotic pathways. Give two examples.
Inactivating mutations in genes coding for apoptotic proteins, such as p53.
Activating mutations in genes coding for anti-apoptotic proteins, such as Bcl-2.
When does collateral sensitivity occur?
resistance to the first one given drug confers a hypersensitivity to an alternate cytotoxic agent to which parental cells were not originally sensitive. The same genetic alteration that caused resistance to one drug now sensitises them to another.
Give an example of collateral sensitivity arising
A patient with metastatic anaplastic lymphoma kinase (ALK)-rearranged lung cancer was resistant to crizotinib because of a mutation in the ALK kinase domain. The patient responded to another drug, lorlatinib. When the tumour relapsed, sequencing of the tumour revealed an ALK mutation resistant to lorlatinib in addition to the mutation resistant to crizotinib. However, the new mutation enhanced binding to crizotinib, negating the effect of first mutation and re-sensitising resistant cancer to crizotinib. The patient received crizotinib again, and cancer-related symptoms resolved.
What are cancer stem cells?
cancer stem cells (CSCs, or cancer cells with stem-cell-like properties) are (or are postulated to be) rare immortal cells within a tumour that can both self-renew by dividing and also give rise to many cell types that constitute the tumour and can therefore form tumours. Only a small subset of cells can give rise to a new tumour.
