Penn investigators finger a 'turncoat' molecule's key role in Tykerb resistance

Researchers at the University of Pennsylvania Perelman School of Medicine found that the interplay between a well-known tumor suppressor molecule and an oncogene may explain why breast cancer patients become resistant to Tykerb (lapatinib).

Specifically, they concluded that lapatinib, which activates the tumor suppressor FOXO in a breast cancer cell line (HER2+), commonly leads to FOXO evolving into a turncoat molecule that desensitizes patients to the drug. This secondary behavior working via an epigenetic regulator turns on the expression of oncogene c-Myc.

The work was published in the journal Cancer Cell, driven by senior author Xianxin Hua, who is a professor of cancer biology at the school.

"We found that an epigenetic pathway is crucial for growth of HER2+ cells and this epigenetic factor reduces sensitivity of the cancer cells to lapatinib, a HER2 inhibitor," Hua said. "We need to understand how the body initially responds to these drugs and why there is a relapse and devise a new tool to fix that."

HER2+ is a cell line initially derived from a patient with an overactive human epidermal growth factor receptor 2. The efficacy of drugs like lapatinib in these patients is limited since the tumorigenic cells quickly adapt.

Once thought of as a beneficial molecule in controlling the spreading of cancer cells, FOXO may now be viewed as an early regulator to drug desensitization. "Now that we know about this triangle among FOXO, c-Myc, and the epigenetic pathway, we can stop c-Myc with an epigenetic inhibitor," Hua said.

These findings by Hua and his team add another angle to consider when thinking about drug development in the HER2 cancer pathway.

- here's the release
- read the research abstract

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