Addition of PI3K Inhibitor May Prevent or Delay Resistance to Therapy in HER2+ Breast Cancer

Carlos L. Arteaga, MD

A new study found that patients with HER2-positive breast cancer who are receiving anti-HER2 therapy could prevent or delay resistance when a phosphatidylinositol-3 kinase (PI3K) inhibitor is added during treatment.

The research was published in the journal Cancer Research.

Amplification of the HER2 gene is associated with increased cell proliferation, tumor invasion, angiogenesis, and resistance to anti-cancer therapy. Currently, trastuzumab is approved to treat patients with HER2-positive breast cancer.

“HER2 breast cancer is a subtype of breast cancer for which we have an increasing number of effective treatments, including trastuzumab, an antibody that targets HER2,” said Carlos L. Arteaga, MD, director of the Breast Cancer Program at Vanderbilt-Ingram Cancer Center in Nashville, Tennessee, in a statement. “Unfortunately, many breast cancer tumors learn how to resist this therapy.”

Arteaga and his colleagues used this study to determine whether aberrant signaling through the PI3K pathway could be a mechanism of resistance to trastuzumab. The researchers used breast cancer models of trastuzumab resistance with different modes of aberrant PI3K activation to determine whether a small molecule PI3K inhibitor called XL147 alone or in combination with trastuzumab had any effect.

The researchers found that when PI3K was inhibited, the ability of tumor cells to proliferate was reduced. Additionally, the PI3K inhibitor was able to induce cell death in trastuzumab-resistant cells. When the two agents were combined, the effects were superior to those seen when XL147 was given alone.

Using this knowledge, the researchers measured pretreatment levels of survivin in HER2-positive breast cancer tumors. High pretreatment levels of survivin were associated with a poor response to therapy.

“We found that the trastuzumab-resistant cells in which the PI3K pathway was activated had high levels of an anti-death protein called survivin,” Arteaga said. “This implied that if we could get levels of survivin to decrease, these cells would become sensitive to treatment.”

The researchers suggested that simultaneously inhibiting both HER2 and PI3K could be associated with better outcomes, although more research into this association needs to be performed before integrating this into clinical practice.

Chakrabarty A, Bhola NE, Sutton C, et al. Trastuzumab-resistant cells rely on HER2-PI3K-FoxO-survivin axis and are sensitive to PI3K inhibitors [Published online ahead of print November 29, 2012]. Cancer Res. doi: 10.1158/0008-5472.CAN-12-2440.