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Predictability of resistance to anticancer drugs

Researchers have explored the predictability of genetic versus nongenetic resistance mechanisms to anticancer drugs in melanoma.

Development of resistance

Metastasis is the major source of cancer-related deaths and remains one of the most important clinical challenges. Despite advances in cancer care, the vast majority of patients who initially respond to treatment, later develop resistance. Resistance is largely due to the fact that most available therapies, even when combined, leave a reservoir of residual cancer cells behind. This is known as minimal residual disease (MRD) and ultimately results in patient relapse.

The most common explanation for this is the evolution of resistance caused by genetic alterations. Until recently, it was thought that resistance arose exclusively through mutation. Now, evidence is emerging that suggests that resistance against cancer drugs can also arise via nongenetic mechanisms that alter gene expression.  However, how cancer cells choose between the different routes of resistance remains unclear.

Anticancer drug resistance trajectories

In a recent paper, published in Cancer Cell, researchers explored the mechanisms underlying nongenetic drug resistance in melanoma.  

The team found that when melanoma was exposed to MAPK therapeutics, emergence of a transient neural crest stem cell (NCSC) population in MRD coincided with the development of nongenetic resistance. The authors suggested that these NCSCs exhibit epigenetic plasticity, which means that they have an increased ability to select which genes they express. In other words, these cells can reprogram themselves to evade therapeutic pressure.

The researchers identified the signalling pathways that drive the emergence of the NCSCs and promote their survival. They found that the protein Focal Adhesion Kinase (FAK) is critical in this pathway. When the researchers blocked the activity of this protein in patient-derived xenografts, they were able to reduce the occurrence of nongenetic drug resistance.

Overall, these findings highlight an approach that abolishes the nongenetic resistance trajectory in melanoma. They also provide insight into how the cellular composition of MRD impacts the distinct drug resistance evolutionary paths.

Florian Rambow, senior postdoc who contributed to the study, explained:

“These findings have several important clinical implications. Not only did we show a viable way to suppress nongenetic resistance, but we also demonstrated that the presence of specific cells dictates which resistance mechanism is likely to occur. This observation is the key to predicting potential resistance routes in patients and developing personalised therapies.”

Image credit: By vitanovski – canva

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Cancer / Cancer Research / Chemoresistance