Discovery of Drug Resistance Advances Breast Cancer Treatment

A recent study conducted by the VCU Massey Comprehensive Cancer Center has identified an unknown biological mechanism through which breast cancer cells develop resistance to standard treatments. This discovery offers a potential new target for cancer scientists worldwide to develop more effective therapies. The research team also tested a promising new drug combination that achieved complete remission in one breast cancer model resistant to standard treatments and significantly reduced tumor growth in other advanced cancer models.

The study, published in Drug Resistance Updates, highlights the importance of overcoming drug resistance to provide new treatment options for cancer patients who have exhausted current therapies. According to lead researcher Yuesheng Zhang, M.D., Ph.D., HER2-positive breast cancers, which make up about 20% of all breast tumors, often grow and spread more quickly than HER2-negative tumors.

Clinically, there are three main types of drugs approved for treating HER2-positive breast cancer: monoclonal antibodies (such as trastuzumab, known by the brand name Herceptin), tyrosine kinase inhibitors, and antibody-drug conjugates. These drugs are all designed to target the HER2 protein receptor. However, Zhang's team found that these treatments are not strong enough to completely eliminate HER2, which allows tumor cells to continue partnering with other proteins and signaling cancer growth.

Zhang emphasized that the efficacy of current standard treatments is limited. Only a small percentage of patients respond to these treatments, and even those who do respond often develop resistance quickly. This highlights the need to more effectively eliminate HER2 from cancer cells. Additionally, the study identified the EGFR gene family as equally important in these tumors. Effective drugs, according to the research, need to target both HER2 and EGFR receptors to be successful in eradicating the disease.

The study also introduced a novel agent that effectively degrades both HER2 and EGFR, overcoming drug resistance in breast cancer. In one model, the new drug achieved complete remission when used with garadacimab, another type of monoclonal antibody. In other advanced cancer models, the drug reduced tumor growth by nearly 70%, even in cases where the cancer had metastasized to the brain. Zhang noted that this indicates the drug's ability to cross the blood-brain barrier and target brain tumors.

The research team is currently collaborating with the National Cancer Institute to manufacture the drug, aiming for FDA approval and the initiation of clinical trials. While the drug showed promising results in the study, Zhang emphasized that the most significant impact of their research is to inform other scientists about this new mechanism in HER2-positive breast cancer. This information could help in developing other drugs targeting this specific vulnerability, improving patient outcomes.

The study could propel the field forward, enabling the development of more effective therapies for drug-resistant HER2-positive breast cancer. Collaborators on this study included scientists from the VCU School of Medicine, the VCU School of Pharmacy, Roswell Park Comprehensive Cancer Center, and the Institute of Curie in France.