Possible Reasons Why Tyverb/Tykerb Fails as Breast Cancer Monotherapy Explored in Study

Possible Reasons Why Tyverb/Tykerb Fails as Breast Cancer Monotherapy Explored in Study

Lapatinib, an approved medicine for advanced breast cancer available under the brand names Tyverb in Europe and Tykerb in the U.S., can sometimes cause breast cancer cells to grow under laboratory condition. In a new study, researchers examine how this could happen.

The findings help explain why a treatment approved as a combination therapy for HER2-positive cancers failed clinical trials as a stand-alone treatment. They may also lead to better HER2-targeting approaches in the future, the scientists report.

“If certain breast cancer drugs can cause cancer cells to grow more rapidly in particular circumstances in the lab, we need to evaluate carefully if that might happen in subsets of patients as well,” Jeroen Claus, study lead author at the Francis Crick Institute in the U.K., said in a press release. “Determining these risk factors could help doctors decide which patients may benefit most from these drugs.”

The study, “Inhibitor-induced HER2-HER3 heterodimerisation promotes proliferation through a novel dimer interface,” was published in the journal eLife.

Nearly 20 percent of breast cancer cases are caused by an excess of the HER2 factor. The receptor, which regulates cell division, is increased by up to 1,000-fold in certain breast cancers, causing cells to divide uncontrollably and promoting tumor growth.

Several approved medicines target HER2 and block its signals in breast cancer. Herceptin (trastuzumab) and Kadcyla (ado-trastuzumab emtansine), for example, bind the receptor on the outside of the cell. But other therapies, called kinase inhibitors, work by preventing HER2 signals inside the cell.

Tyverb is a kinase inhibitor approved for HER2-positive breast cancers in combination with chemotherapy and other medicines. But the treatment fails to show efficacy when used alone.

“As many breast cancers are triggered by HER2, drugs blocking its action have become cornerstone treatments for these diseases and they’ve shown great success. But sometimes these treatments can stop working, so there is a pressing need to develop new drugs that can overcome this issue ,” said Justine Alford with Cancer Research UK.

Researchers tackled the mechanisms underlying the failure of Tyverb in clinical trials using an array of strategies that involved biochemistry and biophysics, as well as computer modeling.

They found that Tyverb causes HER2 receptors to pair with another receptor of the same family, called HER3. The two receptors, once coupled, respond very actively to a growth factor commonly associated with breast cancer, called neuregulin. The signaling from the HER2–HER3 pair tells cells to divide, even faster than in the absence of this treatment.

These results suggest that breast cancer patients whose cells do not trigger an HER3 increase may respond better to Tyverb therapy, and they may help to design new therapies targeting HER2 or HER3.

“In recent patient studies, HER2 targeted therapies that combined lapatinib with the antibody treatment trastuzumab successfully controlled HER2 positive breast cancers at first, but did not improve longer term disease-free survival. Our new findings could help us design future studies to improve combined HER2 targeted therapies,” said Tony Ng, a clinician scientist at the School of Cancer and Pharmaceutical Sciences at King’s College London (KCL), and study co-lead author.

“Although our study was in breast cancer cells, it gives us new insights into the nuts and bolts of what happens to HER2 when you try to block it and raises some interesting questions around how we should approach designing drugs against HER2 positive breast cancer in the future,” added Peter Parker, a study co-senior author and group leader at the Crick Institute and KCL.