Identification of a promising approach to prevent breast cancer recurrence

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Breast cancer treatment outcomes have improved over the years, but a proportion of breast cancers still recur even after long periods without signs of cancer remaining latent in the body. Finnish cancer researchers have discovered a mechanism that wakes up these dormant breast cancer cells and demonstrated that preventing this mechanism can significantly improve treatment outcomes in experimental models.

Although breast cancer treatment outcomes have improved significantly with new research-based therapies, it remains the second most common deadly cancer among women. A particular challenge in the treatment of breast cancer is disease recurrence. Even when treatment appears to be successful and the cancer is considered to have disappeared, it can return years later, either locally or, in the worst cases, by spreading to other parts of the body, such as the brain.

The reasons why dormant breast cancer cells wake up even after several years are not well understood. However, identifying these reasons could provide the opportunity to develop new therapies to prevent cancer recurrence.

Activity of the DUSP6 protein associated with the awakening of breast cancer cells

A recently published Finnish study provides important new information on how breast cancer cells belonging to the HER2-positive subtype can wake up during treatment.

The research group led by Jukka Westermarck, Professor of Cancer Biology at the Turku Bioscience Center and InFLAMES research flagship at the University of Turku and Åbo Akademi University, addressed this research question by treating cancer cells from the breast sensitive to treatment with the HER2 inhibitor for nine months and monitoring how these cancer cells were able to restart their growth during treatment.

By sequencing molecular changes in the cells, the group identified the protein DUSP6, whose expression closely tracked the development of resistance to the treatment. The principal investigator Majid Momeny was also able to show that when the activity of the DUSP6 protein was blocked during cancer treatment, breast cancer cells lost their ability to grow. Blocking the protein also made previously treatment-resistant cancer cells more sensitive to HER2 inhibitors. Another important finding is that by inhibiting DUSP6, it was possible to slow the growth of breast cancer metastases to the brain in mouse models.

“Based on our results, blocking the DUSP6 protein could therefore provide a basis for effective combination therapy also in cases of HER2 breast cancer that have already lost their response to treatment,” explains Professor Westermarck.

The importance of the study is highlighted by the group's access to experimental drug molecules that inhibit the DUSP6 protein. By administering the drug, the researchers demonstrated that the protein could be inhibited in mice without significant side effects. The drug has been shown to significantly enhance the therapeutic effect of several existing HER2 inhibitors.

“The molecules we used in this study are not yet suitable for treating patients, but these recently published basic research results provide important evidence that DUSP6 is a very promising target protein for future cancer drug development and that it deserves to be studied,” continues Westermarck.

Reference: Momeny M, Tienhaara M, Sharma M et al. DUSP6 inhibition overcomes neuregulin/HER3-induced therapeutic tolerance in HER2+ breast cancer. EMBO Molec Med. 2024. do I: 10.1038/s44321-024-00088-0

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