The HDAC2 protein was found to be key in this process, as it facilitates the activation of FOXA1 by HER2/HER3 signals; therefore, blocking HDAC2 could help reverse tumor resistance.
The researchers propose that combining hormonal therapies with HDAC inhibitors (such as romidepsin) or with drugs that block HER2/HER3 could improve the effectiveness of treatment in patients with HER2-low tumors. Photomontage: Medicine and Public Health Magazine.
A team from the Research Center of Cancer (CSIC-University of Salamanca-FICUS) has identified the molecular process that allows certain tumors to mama become resistant to conventional hormonal treatments.
The study, published in Nucleic Acids Research, reveals how some growth signals modify the behavior of the tumormaking it capable of continuing to grow even when hormonal action is blocked.
The molecular switch that changes the rules of the game
Research shows that a protein called FOXA1, which acts as a cellular switch regulating tumor growth, radically changes its behavior depending on whether or not it carries a “chemical mark” known as acetylation.
When is protein It loses this mark, becomes more active and establishes a dangerous alliance with two well-known receptors in oncology: HER2 and HER3. This molecular collaboration allows tumor avoid treatments directed against the estrogen receptor, which are the therapeutic basis for the cancer of mama luminal, one of the most prevalent and complex in oncology.
Resistance mechanisms and new therapeutic opportunities
Using cellular and animal models, the team led by doctors Antoni Hurtado and Sandra López verified that the activation of HER2/HER3 causes the deacetylation of FOXA1, which allows it to escape hormonal control and activate genes associated with a worse prognosis.
The study also identifies the essential role of protein HDAC2, which acts as a critical facilitator for HER2 and HER3 signaling to function properly. This finding suggests that blocking HDAC2 could become a new strategy to slow tumor progression.
Towards more effective therapeutic combinations
The clinical implications of this research are significant. The researchers propose that combining drugs that block HER2/HER3 signals with hormonal therapies could reverse resistance in HER2-low tumors, which have intermediate levels of HER2 and require specific therapeutic approaches.
Furthermore, the use of selective histone deacetylase inhibitors, such as romidepsin, has demonstrated in the laboratory the ability to restore hormonal control of cell growth, opening the way to more personalized clinical trials.
This discovery, the result of collaboration between Spanish and Norwegian institutions, establishes the foundations for developing innovative therapeutic approaches.
Combining HDAC inhibitors, such as romidepsin, with conventional hormonal therapies could represent a promising strategy to overcome resistance in patients with HER2-low tumors.
The researchers highlight that these findings could allow in the future to design drug combinations that block HER2/HER3 signals and improve the effectiveness of current treatments.
