University of Hawaii Researchers Identify Strategy to Overcome Antibody-Drug Conjugate Resistance in Breast Cancer
Key Insights
University of Hawaii Cancer Center researchers demonstrated that switching drug types in antibody-drug conjugates can restore treatment effectiveness in resistant breast cancer models.
The study showed that cross-resistance occurs when sequential antibody-drug conjugates use the same DNA-targeting drug class, but switching to cell-division-blocking drugs restores tumor control.
Findings presented at the San Antonio Breast Cancer Symposium offer clinicians evidence-based guidance for selecting second-line antibody-drug conjugate treatments.
University of Hawaii Cancer Center researchers have identified a promising strategy to overcome drug resistance in breast cancer treatment, demonstrating that switching the type of drug attached to antibodies can restore therapeutic effectiveness when initial treatments fail. The findings, presented December 10 at the San Antonio Breast Cancer Symposium, offer clinicians a practical approach for selecting sequential antibody-drug conjugate treatments.
Breakthrough in Drug Resistance Management
The research team built breast cancer models that became resistant to two widely used antibody-drug conjugates, then tested follow-on treatments that carried different drug types. This switch restored activity in laboratory dishes and mouse studies, supporting a practical drug-switching strategy after resistance develops.
"A simple takeaway is this: After a cancer progresses on one [antibody-drug conjugate], choose the next [antibody-drug conjugate] with a different kind of drug," said Jangsoon "Jason" Lee, associate professor and Director of the Preclinical Core at University of Hawaii Cancer Center. "This drug-guided approach could help these smart treatments work longer for patients."
Understanding Cross-Resistance Mechanisms
The study revealed that several approved breast cancer antibody-drug conjugates use the same type of drug—DNA-targeting topoisomerase I inhibitors. This similarity leads to cross-resistance in preclinical settings, making sequential treatments less effective when used in patients with metastatic breast cancer.
Researchers found that switching to a different drug class—cell-division-blocking drugs—combined with antibodies restored tumor control in resistant models. The breakthrough insight showed that the problem wasn't the antibody's ability to locate and enter cancer cells, but rather that the original drug type had stopped working.
Clinical Implications for Treatment Selection
In laboratory models of both Human Epidermal growth factor Receptor 2-positive and triple-negative breast cancer, switching from DNA-targeting drugs to cell-division-blocking drugs restored tumor control, even though tumors still displayed the same surface markers that antibodies use for targeting.
"These findings by our University of Hawaii Cancer Center research team show that drug resistance is not necessarily the end of the line for cancer patients," said Dr. Naoto T. Ueno, University of Hawaii Cancer Center Director. "Choosing the right kind of drug next could help more patients benefit from [antibody-drug conjugates]."
Addressing Clinical Challenges
The research addresses a significant gap in clinical practice. Antibody-drug conjugates are increasingly used in metastatic breast cancer care, but doctors have limited evidence to guide selection of second-line treatments when initial therapies fail. Real-world reports suggest that second antibody-drug conjugates often provide less benefit when they use the same drug type as the first treatment.
Future Clinical Development
University of Hawaii Cancer Center researchers are now collaborating with clinical partners to design studies that match the next antibody-drug conjugate's drug type to how a patient's tumor becomes resistant. This personalized approach aims to provide longer-lasting therapeutic benefits for cancer patients facing treatment resistance.