6.3 Wk 4 - Resistance to chemotherapy Flashcards
Important point
The cancer cells found in tumours can be different, which means some respond to chemotherapy, others may be resistant to therapy and grow/proliferate into resistant tumours.
Broadly what are the two types of resistance?
- Primary resistance
- Secondary resistance
What are the 4 models of drug resistance in cancer?
- Conventional resistance model
- Cancer stem cell model
- Acquired resistance stem cell model
- Intrinsic resistance model
What is the conventional resistance model
Chemotherapy kills a % of th cancer cells, but others are resistant
These resistant cells grow and proliferate to form a tumour comprised of resistant cancer cells
What is the cancer stem model?
- Some cancer stem cells are killed by the cytotoxic chemotherapy, some cancer stem cells are not.
- Those resistant cancer stem cells which are not killed, have offspring, which grow and proliferate to form tumour comprised of resistant cancer cells
What is the acquired stem cell resistance model?
- Some cancer stem cells are killed by the cytotoxic effect of the chemotherapy
- Some cancer stem cells are not killed, they are resistant
- These stem cells have off spring, which grow and proliferate to form tumours comoprised of resistant cancer cells
- Some of the resistant stem cells are also mutated which cause a build up of new mutated cancer cells in the tumour.
What is the intrinsic resistance model?
The worst type of resistance
Intrinsic resistance occurs when chemotherapy has not impact on cancer cells
In very simple terms how do cancer cells develop resistance?
- Block the drug from entering the cell
- Kick the drug out of the cell
- Repair any damage done to the DNA by the drug
In scientific terms, What are the 8 ways cancer cells can develop resistance to chemotherapy?
Drug Uptake is ↓↓↓:
* Receptors on the surface of the cell may be mutated or their maybe altertions in the cell membrane lipids
**Drug Efflux is ↑↑↑ **
* Cancer cells may overexpress ATP-binding cassette (ABC) transporters, such as P-glycoprotein, which actively pump chemotherapy drugs out of the cell,
**Enhanced DNA Repair **
Cancer cells may be able to repair the damage to DNA caused by cytotoxic chemotherapy
Altered Drug Targets
Cancer cells may undergo genetic mutations or alterations that result in changes to the molecular targets of chemotherapy drugs, making them less susceptible to the drugs’ effects.
**Activation of Survival Pathways: **
Cancer cells can activate survival pathways, such as the PI3K/AKT or MAPK pathways, in response to chemotherapy-induced stress, allowing them to evade cell death and continue proliferating.
**Heterogeneity of Tumor Cells: **
Tumors are composed of heterogeneous populations of cancer cells with varying genetic and molecular characteristics. Subpopulations of cells may inherently exhibit resistance to chemotherapy, allowing them to survive and proliferate despite treatment.
**Microenvironmental Factors: **
The tumor microenvironment, including factors such as hypoxia, acidity, and interactions with stromal cells, can influence the response of cancer cells to chemotherapy and contribute to treatment resistance.
Epigenetic Changes Alterations in gene expression patterns mediated by epigenetic mechanisms, such as DNA methylation and histone modifications, can confer resistance to chemotherapy drugs
What are 2 genetic changes which might induce resistance?
A Oncogene **gains function **when mutated
Epidermal growth factor receptor (EGFR) is an oncogene when Mutated EGFR….ptomotes angiogenesis
* A Tumour suppressor gene, **loses function,** when mutated. ○ P53 is a tumour suppressor gene ○ Mutated P53…. supresses apoptosis, promoting cancer growth.
What is multi drug resistance?
Cancer cells are resistant to multiple forms of chemotherapy
What are the 3 common causes of multi drug resistance
Over expression of ATP dependent efflux pumps
* Chemo ejected from the cancer cell
Upregulation of the MDR 1 gene
* This codes for p-glycoprotein
* Increases activity of ATP driven efflux pumps
* Chemo ejected from the cell
Reduced apoptotic pathways
Reduced drug uptake owing to a defective receptor or alteration in the lipid cell membranes
What do you do to try and overcome multi drug resistance?
Design a drug regimen which targets different parts of the cell cycle
* i.e. different modes of action.
Complementary modes of action rather than competing modes of action tarhetong the same cell cycle.
What is an example of 3 drugs used in combination with complementary modes of action
- Fluourouracil - Inhibits thymidylate synthase, preventing DNA synthesis
- Epirubicin - Forms a complex with DNA by intercalating between base pairs
- Cyclophosphamide - Forms DNA and RNA cross links (Not cell cycle specific)
What are the 4 drugs which might be used to treat Hodgkins lymphoma?
**Doxorubicin (Adriamycin): **
An anthracycline chemotherapy drug that works by interfering with DNA replication and inhibiting the growth of cancer cells. (S Phase)
**Bleomycin: **
Works by damaging the DNA of cancer cells, leading to cell death. (M Phase)
**Vinblastine: **
A vinca alkaloid chemotherapy drug that disrupts the formation of microtubules, essential structures for cell division, thereby inhibiting the growth of cancer cells. (G2 phase)
Dacarbazine:
A chemotherapy drug that works by damaging the DNA of cancer cells, leading to cell death. (None cell cycle specific)
What are the 2 types of resistance often associated with Doxorubicin?
Modulates drug uptake into the cell by:
Overexpression of the multi drug resistance 1 receptor (MDR-1 receptor)
- Codes for p-glycoprotein
- This results in increased ATP which fuels increased efflux pump activity
- Ejecting Doxorubicin from the cancer cell
Increased rate of DNA repair by cancer emergency response genes
*Reducing apoptosis
What is one way methotrexate might develop resistance?
The cancer cell over express dihydrofolate reductase
Even if Methotrexate gets into the cell, it is unable to cope with the over expression of dihydrofolate reductase
This leads to an increased proliferation of cancer cells despite methotrexate treatment.
What are two ways Cisplatin might develop
The Copper transporter 1 (CTR-1) helps Cisplatin enter the cancer cell
When there is a mutation or deletion of the cell CTR-1
* Uptake of Cisplatin into the cell is reduced
Sulpher molecules bind with Cisplatin in the cancer cell
* Promoting increased efflux
* Chemotherapy ejected from the cell.
70% of ovarian cancer is resistant to Cisplatin.
What is the mechanism by which resistance occurs with Herceptin
The receptors on the surface of the cancer cell become truncated, which means the Herceptin is unable to bind with the receptor
Leading to upregulation of signal transduction pathways.
How has the problem of resistance with Herceptin been overcome?
- Lapatinib
- TKI
- Able to cross cell membrane
- Truncated receptors not involved in the drugs path into the cell.
What is the main difference between Herceptin and Lapatinib?
Herceptin is a monoclonal antibody which targets HER2 breast cancer
Lapatinib is a tyrosine kinase inhibitor (TKI) which can target both HEr1 and HER2 breast cancer.
Why might cancer cells continue to grow and proliferate whilst on chemotherapy?
The time between each cycle is too long.
Ideally this interval should be no longer than it takes for bloods to recover
Maybe that some patients respond differently to others and environmental factors
Patients have had a surgical resection (Removal) but micro- disease remains.
What is the cell kill hypothsis?
- Cancer cells recover between cycles
- If there are delays in treatment cancer cell numbers increase furtherLess likely to see poisitive response to chemo
Note
* This can lead to resistance
* Partial exposure to chemotherap - May lead to mutations which ovrcome the mechainsm of action
* Cells multply, resistance is confered to the new cells
* Tumour is populated with resistant cells
