Cancer cells may begin evading therapy much earlier than previously understood, according to research from the Institute for Systems Biology published in Nature Communications. The study shows that treatment itself triggers a stress response, driving some cancer cells into a temporary drug-tolerant state before genetic resistance develops.
Researchers tracked melanoma cells exposed to BRAF-targeted therapy using high-resolution, time-series multi-omics and computational modelling, creating what they describe as a “molecular movie” of the escape process. Rather than comparing cells only before treatment and after resistance emerged, the team observed the transition in real time.
The findings revealed that melanoma cells undergo a reversible shift away from their original drug-sensitive identity into a more primitive, therapy-tolerant state through two sequential “transcriptional waves” that progressively reorganise gene activity. When the drug was removed, cells returned by a different route, retaining a form of “molecular memory” of prior treatment.
At the centre of this adaptive response is NF-κB, a regulator of cellular stress and survival. Targeted therapy disrupts antioxidant defences, leading to oxidative stress that activates NF-κB. This triggers widespread changes in gene regulation, recruiting epigenetic enzymes that modify chromatin, the packaging system determining which DNA regions are accessible. One key target is SOX10, a transcription factor essential for maintaining melanocytic identity.
The researchers found evidence that similar stress-driven pathways operate in lung and colon cancers, suggesting a broader resistance mechanism. They propose that combining targeted therapies with drugs disrupting these epigenetic programmes could prevent cancer cells from entering the escape state, potentially extending treatment effectiveness across multiple cancer types.
Source: Medical Xpress / Institute for Systems Biology (Nature Communications, 2026)
Researchers tracked melanoma cells exposed to BRAF-targeted therapy using high-resolution, time-series multi-omics and computational modelling, creating what they describe as a “molecular movie” of the escape process. Rather than comparing cells only before treatment and after resistance emerged, the team observed the transition in real time.
The findings revealed that melanoma cells undergo a reversible shift away from their original drug-sensitive identity into a more primitive, therapy-tolerant state through two sequential “transcriptional waves” that progressively reorganise gene activity. When the drug was removed, cells returned by a different route, retaining a form of “molecular memory” of prior treatment.
At the centre of this adaptive response is NF-κB, a regulator of cellular stress and survival. Targeted therapy disrupts antioxidant defences, leading to oxidative stress that activates NF-κB. This triggers widespread changes in gene regulation, recruiting epigenetic enzymes that modify chromatin, the packaging system determining which DNA regions are accessible. One key target is SOX10, a transcription factor essential for maintaining melanocytic identity.
The researchers found evidence that similar stress-driven pathways operate in lung and colon cancers, suggesting a broader resistance mechanism. They propose that combining targeted therapies with drugs disrupting these epigenetic programmes could prevent cancer cells from entering the escape state, potentially extending treatment effectiveness across multiple cancer types.
Source: Medical Xpress / Institute for Systems Biology (Nature Communications, 2026)
