Researchers at the Institute for Systems Biology (ISB) announced on Apr. 16 that cancer cells can rapidly adapt to drug treatment by shifting into a temporary drug-tolerant state, according to a new study published in Nature Communications.
The findings are significant because they suggest that resistance to cancer drugs may begin much earlier than previously thought, potentially affecting the long-term success of targeted therapies. The research highlights how some tumor cells survive initial treatments by reprogramming themselves before permanent genetic mutations arise.
Using advanced time-series multi-omics and computational modeling, the ISB team tracked melanoma cells exposed to BRAF-targeted therapy. They found that instead of waiting for resistance mutations, these cells quickly launch an early survival program within hours or days after treatment begins. "We tend to think of drug resistance as something that happens later, after tumors evolve new mutations," said Wei Wei, PhD, co-senior author and associate professor at ISB. "What we're seeing here is that the escape process begins almost immediately. Cells actively reprogram themselves to survive the initial shock of therapy."
The study revealed that melanoma cells respond to treatment by undergoing a reversible shift from their original identity into a more primitive state tolerant of therapy. This transition occurs through two sequential waves of gene activity changes and is not random but follows an ordered sequence. When drugs are removed, these cells return via a different route and retain a molecular memory of prior treatment.
At the center of this response is NF-κB, which acts as an early trigger converting stress from targeted therapy into widespread changes in gene regulation and cell identity. The researchers suggest that combining targeted therapies with drugs disrupting these epigenetic programs could prevent cancer cells from entering this escape state.
"Resistance may begin not only when cancer cells acquire new mutations, but when treatment itself pushes surviving cells into a stronger, more evasive state," Wei said. "If we can intervene early - at the level of cell-state transitions - we may be able to extend the effectiveness of targeted therapies across multiple cancer types."
