Cancer Resistance, Biomarkers, and Personalised Treatment Flashcards
What is cancer therapy resistance?
It occurs when cancer cells develop resistance to different types of treatment, via various mechanisms. These can be specific genetic/epigenetic changes in the cell, or the tumour microenvironment. The microenvironment includes non-cancerous cells and the proteins expressed by them that may lead to increased cancer cell growth
How can we combat therapeutic resistant?
Use different drugs with different mechanisms
Research how resistance develops to develop drugs to combat
Use combination therapies to target different aspects of the tumour, giving less time for resistance to develop
Personalise treatment
What are the two mechanisms for chemotherapeutic resistance of cancer?
Intrinsic resistance - Some cells have pre-existing resistance mechanisms to cancer and chemotherapy kills the non-resistant cells, allowing the resistant cells to grow
Extrinsic resistance - Chemotherapy induces mutations in the cells that results in them becoming resistant
How do cells decrease drug uptake in order to become resistant to therapy?
Cancer cells upregulate mechanisms that prevent the drug from entering the cell - reduction in membrane transporters and receptors, and reduced endocytosis. Methotrexate (toxic folate analogue) resistance occurs because the folate transporter is mutated. The same occurs for nucleoside analogues.
How do cells increase drug efflux in order to become resistant to therapy?
Cancer cells removes drugs that have entered the cell - P glycoprotein upregulation (cell membrane ATP binding protein pump) results in the increased efflux of many foreign molecules. Pgp overexpression associated with resistance to Pgp substrates (doxorubicin, taxanes, vinca alkaloids). Pgp inhibitors can reverse this type of resistance in vivo. The evidence of Pgp overexpression -> resistance is strong in acute myeloid leukaemia and myeloma, but not solid tumours.
How do cells alter drug metabolism for increased detoxification in order to become resistant to therapy?
Cytarabin (nucleoside analogue for AML) requires phosphorylate by deoxycytidine. Resistance occurs when deoxycytidine kinase levels are reduced, via downregulation or mutation
How do cells alter drug targets in order to become resistant to therapy?
The efficacy of the drug is influenced by the molecular target - mutations or downregulation can promote resistance. Gleevec targets Bcr-Abl in CML, but mutations in the binding site of the protein lead to resistance
How do cells change their cellular pathways in order to become resistant to therapy?
Cisplatin induces DNA damage, so upregulated DNA repair mechanisms can lead to resistance. This can occur due to increased expression of important components like ERCC1.
How do cancer cells evade apoptosis in order to become resistant to therapy?
Inactivating mutations in pro-apoptotic genes eg p53. Also, activating mutations in anti-apoptotic genes eg Bcl-2
What is collateral sensitivity?
When resistance to one drug confers hypersensitivity to another drug that the original cell was not sensitive to. The same alteration causing resistance to one drug causes sensitivity to another
What are cancer stem cells?
They are rare immortal cells within in a tumour that can self renew and give rise to the different cell types that can form a tumour. Only a small subset of cells can give rise to a new tumour. They’re slow dividing so not effectively killed by chemo
Why are cancer stem cells resistant to chemotherapy?
High expression of ATP Binding Casette transporter proteins
High aldehyde dehydrogenase activity, oxidising and detoxifying various substances
Anti-apoptotic protein expression BCL-xl and Bcl-2
Enhanced DNA damage repair
Activation of key pro-survival signalling molecules like NOTCH and NF-kB
What is the role of epigenetics in therapy resistance?
In cancer cells, there’s a high rate of epigenetic change, which leads to diversity in gene expression, which could lead to the development of acquired resistance
Describe the theory behind epigenetically poised persistent tumour sustaining cells
When a heterogenous tumour is treated with a drug, some cells survive due to having epigenetic changes that confer resistance. The surviving cells are epigenetically poised tumour sustaining cells - they have epigenetic modifications that confer resistance and sensitivity. If the resisitance is lost (via deacetylation etc.) then the cells become sensitive and die. Continued treatment can lock in the epigenetic profile, leading to a relapse of resistant cells.
What are cancer biomarkers?
Substances produced by cancer cells, or other cells, in response to cancer. They are usually produced by normal cells too, however, are present in much higher/lower levels in cancer. They’re molecules like DNA, RNA, proteins, biochemical modifications.
