S100–RAGE Inhibition Restored Sensitivity to Treatment in Breast Cancer
S100–RAGE signaling contributes to trastuzumab deruxtecan resistance—targeting the pathway showed promise.
A new Houston Methodist-led study published in Clinical Cancer Research reports a breakthrough in understanding why some patients with metastatic breast cancer fail to respond to a common and important early-stage treatment.
Co-led by Stephen Wong, Ph.D., the John S Dunn Presidential Distinguished Chair in Biomedical Engineering and Professor of Radiology and Medicine at Houston Methodist, the study analyzed 47 patients and 109 pretreatment metastatic lesions treated with trastuzumab deruxtecan (T-DXd).
The team identified S100–RAGE signaling-a pathway that functions as a communication system within cancer cells, helping them stay alive, grow, adapt to stress and resist treatment-as a key driver of early drug resistance in tumors. As T-DXd becomes more common in early treatment of metastatic, understanding why some tumors fail to respond has become increasingly important.
“Our study suggested that S100–RAGE signaling may indicate early resistance to this drug and that even drug combination therapies may be less effective. But the exciting part is that this pathway appears targetable,” Wong said. “Using therapeutic options to block the signaling pathway made the cancer cells sensitive to early-line treatment. In metastatic lab models, therapeutic combination with this early treatment significantly reduced metastatic lesion number, lesion size and overall tumor burden.”
According to the Centers for Disease Control and Prevention, breast cancer is the second most common cancer among women in the United States and the second leading cause of cancer death amongst women. Data also shows that metastatic breast cancer has the lowest survival rate.
Reference: Dong W, Wang S, Chan B, et al. Targetable S100-RAGE signaling mediates intrinsic trastuzumab deruxtecan resistance in metastatic breast cancer. Clin Cancer Res. 2026. doi: 10.1158/1078-0432.CCR-25-4894
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