Survival of the Fittest: The Evolution of Drug Resistant Cancer in Chronic Myeloid Leukemia
““Though they all are different in their mechanism, they all have the same goal of killing the cancerous, rapidly dividing cells.””
Cancer is the abnormal growth and division of cells into a tumour that has the potential to spread throughout the body.1 There are many different types of cancers, and as such, there are many different types of treatments for each one. However, though they all are different in their mechanism, they all have the same goal of killing the cancerous, rapidly dividing cells. For example, radiation therapy uses high doses of radiation to kill cancerous cells and shrink tumours.2 Chemotherapy uses different types of cytotoxic drugs to kill rapidly dividing and growing cells.2 There is also hormone therapy that stops the release of certain types of hormones that cancers use to grow and is often used in breast cancer and prostate cancer.2 Additionally, there is targeted therapy that uses different types of drugs to attack the mutations of the cancerous cells that enable them to grow out of control.2
““Treatments can sometimes produce drug-resistant cancers, in which a cancer becomes immune to a certain drug or treatment.””
However, these treatments can sometimes produce drug-resistant cancers, in which a cancer becomes immune to a certain drug or treatment. Both environmental factors, for example exposure to mutagens or carcinogens, or genetic factors, such as having certain mutations that enable the growth of cancerous cells, can lead to the development of cancerous cells, with mutations that allow them to divide and grow out of control. As the cancer grows and develops, it may acquire other mutations, which creates variation within the population, meaning that different cells in the population will have different mutations. When the cancer is treated, it targets all of these cells, but in doing that it puts selective pressure on the cells that can survive and continue to grow. After the administration of the cytotoxic drug, the remaining, surviving cells are able to resist the treatment. As the only cells remaining, they will multiply such all the future cancerous cells will be drug resistant. For example, in targeted therapy, drugs attack one specific trait of cancer that allows it to grow out of control. However, due to the variation in the population of cancerous cells, there may be cells that do not need that specific trait to survive. So when that drug is used, the are the only cells left surviving and can continuing growing using another trait. Sometimes, cancers can be drug-resistant before treatment. This resistance is referred to as primary resistance, while cancers that become drug resistant are said to have “acquired resistance.”
There are many different ways in which cancers can be drug-resistant. There is drug inactivation as many cancer drugs need to be activated to become cytotoxic.3 The drugs need to go through a change in the body before they can start attacking the cancer. Drug inactivation occurs when the mechanism that is used to activate the drug is stopped, and the drug can not attack the cancerous cells. Another way in which cancer can become drug resistant is by becoming hormone-resistant. In some cancers, like prostate and breast cancer, they grow with the help of these hormones. Hormone therapy acts to starve the cancer by stopping or slowing the production of certain hormones, like testosterone or estradiol. However, some cells can have mutations that enable them to grow without hormones, becoming hormone resistant. Another way in which cancer can become drug-resistant is through the alteration of a drug target.3 Drugs can kill cells by identifying and attaching to them using a certain target site. If there is a cell within the tumour that does not have this specific target, the drug can not reach it to attack it. The cell without the drug target will survive, making the cancer drug-resistant.
Alteration of a drug target occurs in chronic myeloid leukemia. Chronic myeloid leukemia is a type of cancer that develops in the cells that make blood in the bone marrow.4 The myeloid cells produce red blood cells, platelets and white blood cells, excluding lymphocytes. A mutation in myeloid cells can lead to the formation of an abnormal gene called BCR-ABL.4 Chronic myeloid leukemia makes up around 15% of all cases of leukemia and has an incidence of 1.6 per 100,000 people.5 It is most common in adults and is rarely found in children.4
““By inactivating the BCR-ABL pathway, imatinib is able to inactivate other pathways that contribute to cell growth, cell death, and movement of cells...””
The most commonly used treatment for chronic myeloid leukemia is the use of the drug called imatinib, commonly known as Gleevec.6 It acts as an inhibitor of tyrosine kinases, a class of enzymes that add phosphate groups to ATP and act largely to turn on and off cellular functions. Imatinib binds to the tyrosine kinase site on the protein created by the BCR-ABL gene and inactivates it.7 By inactivating the BCR-ABL pathway, imatinib is able to inactivate other pathways that contribute to cell growth, cell death, and movement of cells, disabling the cancer from developing.9 Some of the side effects of imatinib include abdominal or stomach pain, nausea, vomiting, diarrhea, mood changes and muscle aches and pains.9 The drug is effective and the overall survival rate on imatinib is 83%.10
Although the drug is effective, some patients develop drug-resistant cancer to imatinib during their treatment.3,10 Through the use of the treatment, the cancerous cells can become resistant through multiple pathways.11 Alteration of the tyrosine kinase site is one of the possible ways in which the drug can become ineffective. Mutations in the BCR-ABL gene can also alter the site and other mechanisms that are targeted by the drug.3 There are also other possible mechanisms that are not related to the BCR-ABL pathway that can cause imatinib resistance, such as a P-glycoprotein that can transport the drug out of the cell so it cannot do its job properly.12
Though there are many ways that chronic myeloid leukemia can become resistant to imatinib, there are also many other drugs and treatments available. A dual-drug treatment has been proposed by using nilotinib, which is a derivative of imatinib and inactivates the BCR-ABL protein, and asciminib, another inhibitor of the BCR-ABL pathway.13, 14 By using the two drugs at the same time, it is much harder for cells to have mutations that are resistant to both, making it an effective treatment for drug-resistant chronic myeloid leukemia.14 Both drugs target the BCR-ABL pathway like imatinib, but in different areas of the pathway that have not become resistant.
There are also many other drugs that can be used instead of imatinib. There is bosutinib which acts to inhibit cell proliferation and facilitate cell death in chronic myeloid leukemia.10 It has been shown to be an effective first-line drug for chronic myeloid leukemia and may have better response in patients than imatinib.15 There is also chemotherapy as an option for treatment. Chemotherapy was mainly used to treat chronic myeloid leukemia before imatinib was created and is often used when the cancer becomes resistant to imatinib.16 Chemotherapy works to attack all rapid growing cells, and does not target specifics like imatinib or any other targeted therapies. Unfortunately, all these therapies can become resistant just like imatinib. Each therapy has their own individual effect and is chosen based on what works best for the patient, not whether or not it can cause drug resistance.
It is unclear as of now how to stop the development of drug resistance in cancer, including chronic myeloid leukemia. There are many options available to patients presently, but as research continues on the mechanisms that enable cancer development and growth and the treatments for it, there may be even more options in the future or even a solution to drug resistance.
Works Cited:
1. What is cancer? - Canadian Cancer Society. www.cancer.ca. http://www.cancer.ca/en/cancer-information/cancer-101/what-is-cancer/?region=on. Accessed January 27, 2018.
2. Types of Cancer Treatment. National Cancer Institute. https://www.cancer.gov/about-cancer/treatment/types. Accessed January 27, 2018.
3. Housman G, Byler S, Heerboth S, et al. Drug Resistance in Cancer: An Overview. Cancers. 2014;6(3):1769-1792. doi:10.3390/cancers6031769.
4. What Is Chronic Myeloid Leukemia? | Leukemia Types. American Cancer Society. https://www.cancer.org/cancer/chronic-myeloid-leukemia/about/what-is-cml.html. Accessed January 27, 2018.
5. Cortes, J, Silver, R, Khoury, H, Kantarjian, H. Chronic Myeloid Leukemia. Oncology Journal. 2016. http://www.cancernetwork.com/chronic-myeloid-leukemia/chronic-myeloid-leukemia
6. Imatinib Mesylate Monograph for Professionals. Drugs.com. https://www.drugs.com/monograph/imatinib-mesylate.html. Accessed January 27, 2018.
7. Gambacorti-Passerini, C, Gunby, R, Piazza, R, Galietta, A, Rostagno, R, Scapozza, L. Molecular mechanisms of resistance to imatinib in Philadelphia-chromosome-positive leukaemias. The Lacent Oncology. 2003;4(2):75-85. http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(03)00979-3/fulltext
8. Weisberg, E, Manely, P, Cowan-Jacob, S, Hochhaus, A, Griffin, J. Second generation inhibitors of BCR-ABL for the treatment of imatinib-resistant chronic myeloid leukaemia. Nature Reviews Cancer. 2007;7:345-356. https://www.nature.com/articles/nrc2126
9. Imatinib Side Effects. Drugs.com. https://www.drugs.com/sfx/imatinib-side-effects.html. Accessed January 27, 2018.
10. Bitencourt R, Zalcberg I, Louro ID. Imatinib resistance: a review of alternative inhibitors in chronic myeloid leukemia. Revista Brasileira de Hematologia e Hemoterapia. 2011;33(6):470-475. doi:10.5581/1516-8484.20110124. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3459369/
11. Gorre, M, Mohammed, M, Ellwood, K, Hsu, N, Paquette, R, Rao, P, Sawyers, C, Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science. 2001;293(5531):876-880. https://www.ncbi.nlm.nih.gov/pubmed/11423618
12. Hirayama, C, Watanabe, H, Nakashima, R, Nanbu, T, Hamada, A, Kuniyasu, A, Nakayama, H, Kawaguchi, T, Saito, H. Constitutive overexpression of P-glycoprotein, rather than breast cancer resistance protein or organic cation transporter 1, contributes to acquisition of imatinib-resistance in K562 cells. Rharm Res. 2008; 25(4):827-825. https://www.ncbi.nlm.nih.gov/pubmed/17934801
13. Dong, J, Lu, W, Pan, X, Su, P, Shi, Y, Wang, J, Zhang, J. Discovery of novel Bcr-Abl inhibitors targeting myristoyl pocket and ATP site. Bloorg Med Chem. 2004;22(24)6876-84. https://www.ncbi.nlm.nih.gov/pubmed/25464886
14. Rashedy, E, Olotu, F, Soliman, M. Dual drug targeting of mutant Bcr-Abl induces inactive conformation: New strategy for the treatment of chronic myeloid leukemia and overcoming monotherapy resistance. Chem Biodivers. 2018. [Epub ahead of print]. https://www.ncbi.nlm.nih.gov/pubmed/29325229
15. Cortes, J, Gambacorti-Passerini, C, Deininger, M, Mauro, M, Chuah, C, Kim, D, Dyagil, I, Glushko, N, Milojkovic, D, le Courte, P, Garcia-Gutierrez, V, Reilly, L, Jeynes-Ellis, A, Bardy-Bouxin, N, Hocchaus, A, Brummerdorf, T. Bosutinib Versus Imatinib for Newly Diagnosed Chronic Myeloid Leukemia: Results From the Randomized BFORE Trial. J Clin Oncol. 2018; 36(3):231-237. https://www.ncbi.nlm.nih.gov/pubmed/29091516
16. Treating Chronic Myeloid Leukemia. cancer.org. https://www.cancer.org/cancer/chronic-myeloid-leukemia/treating.html Accessed January 27, 2018.
17. Hematopoietic stem cell. wikipedia.org. https://en.wikipedia.org/wiki/Hematopoietic_stem_cell
18. Zahreddine, H, Borden, K. Mechanisms and insights into drug resistant cancer.Front Pharmacol. 2013;14(4):28. https://www.ncbi.nlm.nih.gov/pubmed/23504227
Cite This Article:
Tropak C., Chan G., Palczewski K., Lewis K., Ho J. Survival of the Fittest: The Evolution of Drug Resistant Cancer in Chronic Myeloid Leukemia. Illustrated by L. Nguyen. Rare Disease Review. February 2019. DOI:10.13140/RG.2.2.11428.94089.
