Triple blow

According to a new study conducted by Washington University School of Medicine in St. Louis, an experimental drug compound stimulates immune cells to attack prostate cancer tumor cells in different ways. It activates immune cells, helps them penetrate the tumor and suppresses the ability of cancer cells to use testosterone as an energy source.

Prostate cancer sooner or later develops resistance to standard treatments that block or reduce the level of testosterone that fuels the growth of this tumor. And, like many solid tumors, prostate cancer has also proved resistant to new immunotherapy methods.

A new experimental drug may be useful for patients who do not respond to standard therapy. (R)-9b is a small molecule that blocks the Tnk2 oncogene. Previously, (R)-9b was successfully tested in studies on mice, the authors explained its extremely high efficacy by its ability to reduce or completely eliminate androgen receptor proteins in prostate cancer cells. These receptors capture testosterone, and the cancer cell uses the hormone for growth.

But the mechanism of action of (R)-9b turned out to be more complicated. High efficiency is associated with the deactivation of the Tnk2 gene encoding activated CDC42 kinase 1 (ACK1). ACK1 is involved in androgen receptor expression and immune system management. The researchers bred a strain of mice in which Tnk2 was silenced and ACK1 was completely absent. They noted that there was practically no tumor growth in the animals. Modeling cancer in these mice failed. When they were injected with cancer cells, most did not show any traces of a tumor. Some rodents had tumors, but much smaller in size compared to the tumors of wild-type mice. In this way, the researchers were able to create a sustained immune response against cancer cells.

When mice with normally functioning Tnk2 were implanted with human prostate cancer samples and injected with a drug (R)-9b blocking this gene, the effect was the same: the level of antitumor T cells increased, the number of signaling molecules that allow T cells to penetrate the tumor and kill cancer cells more effectively increased. Tumors in these (R)-9b-treated mice were much smaller than in mice in the control groups.

Since (R)-9b facilitated the penetration of T cells into the tumor tissue, the researchers suggested that strengthening in the form of immune checkpoint inhibitors would make the treatment even more effective, but expectations were not met. It turned out that inhibitors of immune control points activate ACK1, which is blocked by the tested drug (R)-9b. Perhaps this is the key to the low effectiveness of immunotherapy for prostate cancer.

ACK1 activation can also be used in other cancers that do not respond to checkpoint inhibitors, especially with hormone-dependent growth, such as breast cancer. These tumors may respond to (R)-9b, and the authors plan to test this.

Article by D.Sridaran at al. Inhibiting ACK1-mediated phosphorylation of C-terminal Src kinase counteracts prostate cancer immune checkpoint blockade resistance is published in the journal Nature Communications.

Aminat Adzhieva, portal "Eternal Youth" http://vechnayamolodost.ru based on the materials of Washington University in St. Louis: Drug triggers immune cells to attack prostate cancer.