Can Resistance to HER2 Therapy Be Overcome?

HER2 positive breast cancer cells respond to PI3K inhibitor and trastuzumab

(RxWiki News) The standard of care for HER2-positive breast cancer is Herceptin (trastuzumab). Over time, though, this aggressive cancer can become resistant to the medication. New research may have discovered a way around this resistance.

Recent research found that adding a so-called PI3K inhibitor early on in treatment may delay or even prevent resistance to Herceptin therapy for HER2-positive breast cancer.

Researchers also discovered that levels of a protein – known as survivin – may predict which tumors would benefit from this dual treatment.

While this combination therapy may be years away from being available, the research shows progress is being made in treating a relentless form of breast cancer.

"Ask your oncologist about medication resistance."

A study looking into why Herceptin eventually fails in the treatment of HER2-positive breast cancer was led by Carlos L. Arteaga, MD, director of the Breast Cancer Program at Vanderbilt-Ingram Cancer Center in Nashville, Tenn.

HER2-positive breast cancer tests positive for a protein called human epidermal growth factor receptor 2 (HER2). In about 20 percent of breast cancers, the cancer cells make too much of HER2 due to a gene mutation. HER2 promotes the growth of cancer cells. This cancer tends to be aggressive.

Researchers discovered that at some point trastuzumab no longer blocks phosphatidylinositol-3 kinase inhibitor (PI3K) signaling, which promotes cancer growth. When this happens, the medication no longer works, and the cancer starts to grow again.

Dr. Artega and his colleagues theorized that adding a P13K blocker might be a way to delay resistance. To test this theory, the team added a PI3K inhibitor called XL147 alone or in combination with trastuzumab to various models.

They found that interfering with PI3K also interfered with cancer cell growth and killed trastuzumab-resistant cells. Combining XL147 with trastuzumab was more effective against resistant HER2-positive cells than the PI3K inhibitor by itself.

The investigators also discovered that tumors with high levels of a protein called survivin typically did not respond well to treatment.

“This implied that if we could get levels of survivin to decrease, these cells would become sensitive to treatment,” Dr. Artega said in a statement.

PI3K inhibitors, including XL147, are currently in clinical development. Dr. Artega plans to continue testing these medications in combination with other HER2 drugs. His team will also be looking at survivin in HER2-positive breast tumors to see if levels of the protein effectively predict response to combination therapies.

This research was published January 23 in Cancer Research, a journal of the American Association for Cancer Research

This study was supported by an American Cancer Society Clinical Research Professorship grant, Lee Jeans Translational Breast Cancer Research Program, a Stand Up to Cancer Research grant, a Susan G. Komen for the Cure Foundation grant, a Breast Cancer Specialized Program of Research Excellence grant and Vanderbilt-Ingram Cancer Center Support Grant.

Review Date: 
January 24, 2013