Radiotherapy Personalization with Genetic Insights

The 2022 Nature Medicine study reveals that brain metastatic cancer cells from diverse primary tumors overexpress the protein S100A9 within the brain microenvironment, which drives resistance to whole-brain radiotherapy (WBRT) through activation of the NF-κB signaling pathway. This resistance mechanism is mediated by S100A9 binding to its receptor RAGE (receptor for advanced glycation end products), whose expression is induced by radiation. Genetic silencing or pharmacological inhibition of S100A9 or RAGE using the blood–brain barrier–permeable inhibitor FPS-ZM1 effectively sensitizes brain metastases to radiotherapy in experimental models and patient-derived cultures. The study showed that adding recombinant S100A9 to radiosensitive brain metastasis cells increased their radioresistance threefold in vitro.

Analysis of brain metastases from patients with lung cancer, breast cancer, or melanoma demonstrated that higher S100A9 expression correlates with poorer response to radiotherapy, suggesting its potential as a predictive biomarker. Importantly, S100A9 levels in blood samples also emerged as a noninvasive biomarker to stratify patients likely to benefit from radiotherapy. Targeting the S100A9-RAGE-NF-κB-JunB pathway reversed radioresistance and improved therapeutic outcomes at lower radiation doses, reducing toxicity. This molecular framework offers a strategy to personalize WBRT by combining it with radiosensitizers like FPS-ZM1 to enhance efficacy while minimizing side effects. The findings provide a clinically actionable mechanism to overcome radioresistance in brain metastases and improve patient survival.