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When cells divide, the DNA in the parent cell is copied and passed on to daughter cells. While this process is usually very accurate, it is not perfect. Mutations can arise during DNA replication, and if they are not repaired they can be passed on to daughter cells.
Most mutations happen in places that don’t have any important consequences, but sometimes, they happen in genes that make the cell better at growing and dividing potentially leading to cancer.
Cancer is the result of mutations in normal cells, but once the cancer develops that doesn’t mean that mutations stop. Our bodies continue to accumulate mutations over our lifetime and cancer tends to mutate more easily than normal cells so it is constantly changing.
Clonal evolution refers to the process by which tumors change over time and develop different properties such as resistance to treatments. You can find more information on clonal heterogeneity here.
At the annual meeting of the American Society of Hematology, (ASH) 2019, our own Dr. Brian Koffman interviewed Dr. Adrian Wiestner, a senior investigator at the National Institutes of Health, who focuses on treating patients with chronic lymphocytic leukemia (CLL). They discussed clonal evolution in CLL and how it can lead to resistance to certain treatments.
Targeted therapies have been very effective for treating CLL because they act on specific proteins that cause cells to become cancer. However, because targeted therapies are so specific, they can create a bottleneck that selects cells that can survive the treatment.
- Mathematical models predict that any mutation you can think of would be present in at least one cell out of the trillions present in the body. Most mutations will not lead to cancer, but certain combinations of mutations can.
- If we have trillions of cancer cells, they likely all have different mutations. As long as a mutation doesn’t confer a survival advantage, it’s just part of the mix. Once you apply a treatment, cells that are sensitive to it die. Cells that are resistant to it survive and take over.
- For example, ibrutinib inhibits the Bruton tyrosine kinase (BTK) protein. When patients are treated with ibrutinib, cells that need BTK will die. Cells that have mutations that allow them to grow without BTK will survive and may eventually take over.
- This can lead to resistance to the treatment; the disease progresses, and it is genetically different from when treatment started.
- Some people think that combination therapy might help avoid the development of treatment resistance. However, with trillions of cells and mutation combinations, that might not necessarily be true, even with potent combinations.
Because cancer is constantly changing, it is important that our approach to treatment is also flexible. Clonal evolution highlights the need to be able to change treatment strategies when resistance develops. It is really important to have multiple treatment options available. Ideally, those treatments should work through different mechanisms of action.
When one treatment stops working, we want to be able to attack CLL in a different way. Fortunately, scientists are hard a work developing new therapies. Great progress continues to be made in the treatment of CLL.
Please enjoy this interview with Dr. Wiestner from December 2019 at ASH in Orlando, FL.
You can read about some of Dr. Wiestner’s previous research here: The evolutionary landscape of chronic lymphocytic leukemia treated with ibrutinib targeted therapy
Take care of yourself first.
Ann Liu, PhD