A Houston Methodist-led study has identified a biological signaling pathway that may help explain why some metastatic breast cancers resist trastuzumab deruxtecan, a widely used targeted therapy. Published in Clinical Cancer Research, the research points to S100–RAGE signaling as a potential driver of intrinsic drug resistance and suggests that blocking this pathway could restore tumor sensitivity to treatment. The findings may open a new route for identifying patients whose tumors are unlikely to respond and for designing combination therapies that overcome resistance before it becomes clinically apparent.
Trastuzumab deruxtecan, commonly known as T-DXd, is an antibody–drug conjugate designed to target cancer cells carrying high levels of the HER2 protein. The drug uses a monoclonal antibody to recognize HER2 on the tumor-cell surface, then delivers a powerful topoisomerase I inhibitor into the cell. Once released, the payload damages DNA and can kill the targeted cell. T-DXd can also produce a “bystander effect,” in which the drug payload spreads into nearby tumor cells, including some with lower HER2 expression. Despite this sophisticated mechanism, a proportion of patients experience little or no benefit, allowing metastatic disease to continue progressing.
The new study examined 47 patients with metastatic breast cancer and analyzed 109 metastatic lesions collected before treatment with T-DXd. By studying molecular features across these pretreatment tumors, the researchers sought to determine whether resistance could be predicted before therapy began. Their analysis identified heightened activity in the S100–RAGE signaling network in tumors that showed characteristics associated with early resistance. The pattern was not simply a marker of tumor growth; it appeared to represent a coordinated biological program that could help malignant cells survive the stress imposed by anticancer treatment.
S100 proteins are a family of calcium-binding molecules involved in inflammation, cell movement, tissue remodeling and cancer biology. RAGE, or the receptor for advanced glycation end products, is a cell-surface receptor that responds to several molecular signals, including certain S100 proteins. When activated, the S100–RAGE axis can trigger downstream pathways controlling gene expression, metabolism, inflammation, survival and adaptation to cellular stress. In cancer, these signals may create a protective state in which tumor cells repair damage more effectively, avoid programmed cell death and alter their surroundings to support continued growth.
The Houston Methodist team, co-led by Stephen Wong, Ph.D., the John S. Dunn Presidential Distinguished Chair in Biomedical Engineering and professor of radiology and medicine, and corresponding author Hong Zhao, investigated how this signaling system was connected to T-DXd resistance. The researchers combined patient-derived molecular data with laboratory experiments and metastatic models. Their results suggested that tumors with active S100–RAGE signaling could withstand the cellular damage caused by T-DXd more effectively than tumors lacking the same signaling profile. This may help explain why resistance is sometimes present before treatment rather than emerging only after prolonged drug exposure.
The researchers then tested whether the pathway could be therapeutically interrupted. In laboratory experiments, blocking S100–RAGE signaling made resistant cancer cells more vulnerable to T-DXd and other early-line treatment combinations. In metastatic models, combining pathway inhibition with T-DXd significantly reduced the number and size of metastatic lesions as well as the overall tumor burden. These experiments provide a mechanistic explanation for the patient-derived observations, although they do not yet demonstrate that the approach is safe or effective in people.
“Our study suggested that S100–RAGE signaling may indicate early resistance to this drug and that even drug combination therapies may be less effective,” Wong said. “But the exciting part is that this pathway appears targetable.” His comments highlight the study’s central implication: S100–RAGE activity could potentially serve two roles, first as a biomarker for identifying tumors at high risk of treatment failure and second as a therapeutic target that can be inhibited alongside T-DXd.
The distinction between a predictive biomarker and a treatment target is important. A biomarker could help clinicians recognize patients whose tumors are unlikely to respond to T-DXd alone, allowing closer monitoring or enrollment in trials of alternative combinations. A target, by contrast, must be disrupted in a way that produces meaningful benefit without unacceptable toxicity. Because S100–RAGE signaling also participates in normal inflammatory and tissue-repair processes, any drug designed to block it would need to be carefully evaluated for effects on the immune system and other organs. The current findings establish a rationale for that work but are not a clinical recommendation.
Metastatic breast cancer remains a major public-health challenge. Breast cancer is the second most commonly diagnosed cancer among women in the United States and the second leading cause of cancer death among women, according to the Centers for Disease Control and Prevention. Once breast cancer spreads to distant organs, it is generally considered treatable but not curable, and survival outcomes remain substantially worse than for localized disease. As T-DXd and other antibody–drug conjugates move into earlier lines of treatment, understanding why some tumors fail to respond from the outset will become increasingly important.
The study was supported by the National Institutes of Health, the John S. Dunn Research Foundation and the T. T. and W. F. Chao Foundation. Collaborators included researchers from Houston Methodist and Emory University. Further studies will be needed to validate S100–RAGE signaling in larger patient groups, determine whether its activity can be measured reliably in routine clinical samples and identify the safest inhibitors for combination treatment. If those steps succeed, a pathway that currently helps metastatic breast cancer evade therapy could become a visible vulnerability—one that enables physicians to anticipate resistance and attack it before the disease gains ground.
Subject of Research: S100–RAGE signaling and intrinsic resistance to trastuzumab deruxtecan in metastatic breast cancer
Article Title: Targetable S100–RAGE signaling mediates intrinsic resistance to trastuzumab deruxtecan in metastatic breast cancer
Web References: https://aacrjournals.org/clincancerres/article/doi/10.1158/1078-0432.CCR-25-4894/786929/Targetable-S100-RAGE-signaling-mediates-intrinsic
References: Clinical Cancer Research; Houston Methodist; Centers for Disease Control and Prevention
Keywords: metastatic breast cancer, trastuzumab deruxtecan, T-DXd, HER2, S100–RAGE signaling, drug resistance, antibody–drug conjugates, cancer biomarkers, targeted therapy, metastasis
Tags: antibody-drug conjugates in cancer treatmentbiological markers of drug resistancebreast cancer treatment resistancecombination therapies for breast cancerHER2-positive tumor resistancemechanisms of immune evasion in breast cancerovercoming drug resistance in advanced breast cancerpredictive biomarkers for therapy responseS100-RAGE signaling pathwaytargeted therapy in metastatic breast cancertrastuzumab deruxtecan resistance mechanismstumor sensitivity restoration
