Scientists find cause of reduced drug sensitivity in HER2-positive breast cancer

A new study reveals how a common cancer drug used in the treatment of HER2-positive breast cancer can trigger changes in tumor cells that make them desensitized to its effect and lead to relapse.
DNA helix
The researchers found that an anti-cancer drug triggered a series of events that increased the activity of a cancer gene, thus desensitizing the cancer cells to its effects.

The team behind the study, from the Perelman School of Medicine at the University of Pennsylvania in Philadelphia, reports the surprising discovery in the journal Cancer Cell.

They believe their findings, which concern the molecular events triggered by the HER2 inhibitor drug lapatinib (Tykerb, Tyverb), also reveal a possible target to counteract the desensitization of the cancer cells and prevent cancer recurrence.

HER2-positive breast cancers are types of the disease where the cancer cells have a gene mutation that causes them to produce too much HER2 (human epidermal growth factor receptor 2) protein, which promotes tumor growth.

Lapatinib, a drug that is used in combination with other drugs, is a protein tyrosine kinase inhibitor (TKI) that switches off HER2. However, its success is limited by the fact that the cancer cells eventually become unresponsive to its effects, causing the cancer to return.

Lapatinib changes behavior of FOXO tumor suppressor

The new study reveals that the FOXO tumor suppressor molecule changes its behavior when it encounters lapatinib in HER2+ breast cancer cells.

It appears that lapatinib makes FOXO cease to behave like a tumor suppressor and, instead, causes it to team up with gene-regulator molecules to increase the expression of the cancer gene c-Myc.

The result is that the HER2-positive cancer cells become less sensitive to the drug’s intended effect.

The authors refer to their discovery as an epigenetic effect. Epigenetic effects are changes to genes that arise from outside the person’s DNA.

Unraveling the complexity of this interaction offers researchers another point in the HER2 cancer pathway to target.

Senior author Xianxin Hua, a professor of cancer biology, concludes:

“Now that we know about this triangle among FOXO, c-Myc and the epigenetic pathway, we can stop c- Myc with an epigenetic inhibitor. Multiple epigenetic regulators participate in the drug-desensitizing pathway, so they could serve as new targets to improve therapy for this type of cancer.”

Meanwhile, Medical News Today recently learned how a new genetic test called Oncotype DX can predict which patients with early-stage breast cancer are unlikely to benefit from chemotherapy. The test looks for 21 breast cancer-related genes and produces a score that predicts the risk of breast cancer recurrence.

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