When oncologists give certain breast cancer patients a common drug called trastuzumab deruxtecan, or T-DXd for short, it usually works well at first. But sometimes the cancer stops responding, and doctors are left scrambling to figure out why. Now, a team at Houston Methodist Hospital has found an important clue—one that could help more patients survive.
In a study published in the journal Clinical Cancer Research, researchers analyzed 47 patients and 109 metastatic lesions treated with T-DXd. Metastatic means the cancer has spread to other parts of the body, which is the most serious stage. What the team discovered was a communication system inside cancer cells called the S100-RAGE pathway. This pathway acts like a telephone line that tells cancer cells how to stay alive, grow faster, and resist the drugs meant to kill them.
"We identified S100-RAGE signaling as a key driver of early drug resistance in tumors," said Stephen Wong, Ph.D., the John S. Dunn Presidential Distinguished Chair in Biomedical Engineering at Houston Methodist and co-leader of the study. "Our study suggested that S100-RAGE signaling may indicate early resistance to this drug and that even drug combination therapies may be less effective."
Here's where things get hopeful. The researchers found a way to interrupt that phone call. By blocking the S100-RAGE pathway using targeted therapies, they were able to make cancer cells sensitive to treatment again. In experiments with lab models that mimic metastatic breast cancer, combining this blocking approach with early-line treatment significantly reduced the number of metastatic lesions, shrunk their size, and lowered overall tumor burden.
"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."
This discovery matters because breast cancer is the second most common 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. Metastatic breast cancer has the lowest survival rate of all breast cancer stages.
Researchers from Emory University also contributed to the work, which was supported by the National Institutes of Health and several foundations. The team is now hoping their findings will lead to new treatment strategies that could help patients whose cancers have stopped responding to current drugs.
"The goal is to give patients more effective options when their cancer becomes resistant," Wong said. "If we can intercept that resistance early, we may be able to improve outcomes for many people facing this disease."