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Study: Melanoma Cells Can Quickly Adapt Without Immediate Genetic Changes to Resist Anti-Cancer Drugs
Our researchers found that melanoma cells grown in petri dishes in a lab were able to escape treatment using different non-genetic pathways.?
The Challenge
More than half of?melanomas?contain a mutation in the?BRAF?gene, which regulates the cell cycle, the series of events that take place in a cell as it grows and divides. A mutation in this gene allows cells to grow out of control.
The discovery of this cancer-causing mutation led to the development of?targeted drugs called BRAF inhibitors,?which stop the growth of cancer cells that have this genetic defect. When?melanomas with mutant?BRAF?are treated with a BRAF inhibitor, they typically shrink. But the problem is that some cancer cells become resistant to the drug’s effects and keep growing, causing the tumor to return.
The Research
American Cancer Society (大象tv) grantee, Sabrina Spencer, PhD, is committed to better understanding what signals in a cell determine whether the cell divides,? via a process known as mitosis, or whether it enters a non-dividing state.
While much of the field of cancer biology has focused on how genetic mutations drive drug resistance, the signaling plasticity involved in non-genetic drug resistance is only now beginning to be appreciated."
Her motivation is simple—cancer is a disease where the tightly regulated process of cell division goes awry. Work from her 大象tv-funded study contributed to a paradigm-shifting concept that Science.?The study found that cells sense growth stimulators throughout their entire cycle leading up to cell division, not just during a narrow window. This new understanding about how cells proceed through mitosis might provide new clues as to how cell division could go awry, and in the end lead scientists to new targets for treatment.
A better understanding of signals that dictate whether a cancer cell divides, doesn’t divide, or dies also has implications for how cancer patients respond to treatment, another research area where Spencer and her colleagues are innovating both conceptually and technically.
Many studies have looked specifically for gene changes that may make certain cancer cells resistant to targeted therapies, but in Nature Communications, Spenser and her colleagues looked at whether non-genetic mechanisms (i.e., a process not relying on changes to the DNA) of drug resistance exist. They used a novel method, developed in the Spencer lab, to individually track thousands of melanoma cells that were treated with a BRAF inhibitor for several days . This approach revealed that melanoma cells are able to adapt rapidly and then evolve in response to treatment in part by additional genetic changes.??
They found that melanoma cells grown in petri dishes in a lab were able to escape treatment using a variety of different non-genetic pathways. By targeting components within some of the pathways, the researchers could reduce the number of cells that survived treatment.
Forty genes that escaped treatment were found at higher levels in the cells, providing an abundance of potential targets for future treatments. Importantly, the researchers expanded their analyses to include patient biopsies of melanomas with a common BRAF mutation (V600E) and discovered that some cells were able to escape using pathways identified from their earlier commercial cell studies. In addition, they found that 5 of the 40 genes that escaped treatment are associated with reduced patient survival.
Why It Matters
Understanding how melanoma cells adapt to targeted therapies and evade their actions through non-genetic mechanisms provides new opportunities to block these adaptive pathways and, in doing so, potentially prevent drug resistance. Since BRAF mutations are not limited to melanomas, these findings will likely have broader cancer treatment implications.