Targeting DUSP6 to Prevent Breast Cancer Recurrence

Although the results of breast cancer treatments have improved over time, a percentage of cases still reappear after extended periods without any indication that the disease is still dormant in the body. These sleeping breast cancer cells are roused by a mechanism that Finnish cancer researchers have uncovered, and they have shown that blocking this mechanism can greatly enhance treatment outcomes in animal models.

Even while new research-based treatments have greatly improved treatment outcomes, breast cancer is still the second most prevalent malignancy to kill women. The disease’s recurrence presents a unique challenge in the treatment of breast cancer. Years later, the cancer may recur locally or, in the worst case scenario, spread to other regions of the body, including the brain, even when treatment seems to be working and it is thought to have eradicated.

It is unclear why breast cancer cells that have lain dormant for years suddenly come to life. Finding these causes, though, might offer a chance to create fresh treatments to stop cancer from coming back.

Protein activity of DUSP6 linked to the arousal of breast cancer cells

Important new information on the ability of HER2-positive breast cancer cells to awaken during therapy has been revealed by a recently published Finnish study.

As part of their investigation into this research question, the research team headed by Jukka Westermarck—a professor of cancer biology at the Turku Bioscience Centre and the head of the InFLAMES research flagship of the University of Turku and Åbo Akademi University—treated breast cancer cells that were susceptible to treatment with HER2 inhibitors for nine months, observing how the cancer cells were able to resume growth during the treatment.

The team discovered the DUSP6 protein through sequencing the molecular alterations in the cells; this protein’s expression closely coincided with the emergence of treatment resistance. Prominent scientist Majid Momeny was also able to demonstrate that breast cancer cells lost their growth potential when the DUSP6 protein’s function was inhibited during cancer treatment. The cancer cells that had previously resisted treatment became more susceptible to HER2 inhibitors when the protein was blocked. Another significant discovery was the ability to decrease the formation of breast cancer metastases in mice models of the brain by blocking DUSP6.

“Based on our findings, blocking the DUSP6 protein could therefore provide a basis for effective combination therapy also in HER2 breast cancer cases that have already lost response to treatment.” – Jukka Westermarck, Professor of Cancer Biology, Turku Bioscience Centre

The group’s access to investigational pharmacological compounds that block the DUSP6 protein emphasizes the significance of the study. The researchers showed that the protein could be suppressed in mice without causing noticeable negative effects by giving them the medication. Significantly, the medication was demonstrated to improve the therapeutic efficacy of a number of HER2 inhibitors that are currently in use.

“The molecules we used in this study are not yet suitable for patient treatment, but these newly-published basic research results provide important evidence that DUSP6 is a very promising target protein for future cancer drug development and worth investigating,” Westermarck continues.

For more information: DUSP6 inhibition overcomes neuregulin/HER3-driven therapy tolerance in HER2+ breast cancer, EMBO Molecular Medicine, http://doi.org/10.1038/s44321-024-00088-0