Dual backup circuits in cancer cells that allow the cells to evade the effects of a common cancer drug have been discovered by scientists at Dana-Farber Cancer Institute and colleagues in Japan. Using targeted therapies to disconnect those circuits may improve or re-establish the cancer drug’s effectiveness, according to a study published in the September 7 issue of Science Translational Medicine.
Research was focused on the drug cetuximab, an effective therapy for colorectal cancer or squamous cell cancer of the head and neck. However, the benefits of cetuximab seldom last longer than a year, and some patients gain no benefit from the drug. Why cancers that initially respond to cetuximab become resistant to it, and how to overcome such resistance, has been unknown until now.
Researchers led by Pasi Jänne, MD, PhD, of Dana-Farber, and Kimio Yonesaka, MD, PhD, of Kinki University School of Medicine in Osaka, Japan, found that in some cetuximab-resistant cancer cells, the “stop growing” signals triggered by cetuximab were being intercepted by a protein known as ERBB2, which was actively sending “grow” signals. The team discovered that ERBB2’s strength developed from either an abundance of the protein’s parent gene, HER2/neu, or by a related protein, ERBB3, when prompted by high levels of the protein heregulin. The “grow” messages are unaffected by cetuximab in both cases.
“ERBB2 activates a critical signaling pathway that is not normally blocked by cetuximab, and in this way subverts cetuximab’s function,” says Jänne. “Because ERBB2 isn’t affected by cetuximab, this is an easy way for cancers to become resistant to the drug.”
For cancers that are cetuximab-resistant from the beginning or for those that develop resistance over time, study findings suggest that using cetuximab with ERBB2-inhibiting drugs may be an effective therapy. Several of these inhibitors have already gained approval. Others are undergoing clinical study.
“We hope the findings of our study will inspire the development of clinical trials aimed at overcoming cetuximab resistance,” Yonesaka remarks. “We’ve identified biomarkers that can be used to select cetuximab-resistant patients who may benefit from a combination of cetuximab and ERBB2 inhibitors.”
Source: Dana-Farber Cancer Institute.