Breast Cancer Drug Flips Switch to Sensitize Cells to Immunotherapy

New evidence demonstrates how experimental drug AMPI-109 kills triple-negative breast cancer cells by “flipping the switch” on the enzyme PRL-3 in the TNF-R1 pathway.

Scientists have known for decades about the paradoxical signaling pathway TNF-R1, whose activation can either help a cell survive, or lead to cell death. However, little has been known about how this signaling occurs, especially with cancer cells.

In a new study published in Oncogenesis, researchers have uncovered new evidence on how this process works.

“We have observed that one regulator of this process in triple-negative breast cancer cells may be the activity of PRL-3,” said first study author Hamid Gari, PhD. “With this gene active, cells survive. With PRL-3 inactivated, cells senesce and eventually die.”

During the study, researchers found that the PRL-3 enzyme is able to set in motion a set of genes that recruit elements of the immune system in order to enhance tumor growth during good times, and lets cancer cells sleep through bad times.

“Hamid’s studies knocked down the gene PRL-3 in triple-negative breast cancer cells using genetic techniques, but the drug does something analogous by blocking PRL-3 function,” said senior study author James R. Lambert, PhD. “Our studies suggest AMPI-109 reprograms the cell to enter senescence but then they keep going past this state and into apoptosis.”

Although immunotherapies are increasing in usage, cancer cells have the ability to evade the immune system, allowing them to subsist and thrive in challenging tumor tissue conditions.

“Our studies propose that by inhibiting PRL-3 activity, such as with AMPI-109, it may serve as a ‘flag’ to signal the immune system where the tumor is, and in essence could sensitize tumors to immunotherapy,” Gari said. “The result is a 2-hit strategy to expose the tumor and then allow the immune system combat it.”

Currently, the research group has applied for NIH funding and are working toward company funding to test the drug’s safety. If the results continue to be promising, AMPI-109 could be a key drug in targeting triple-negative breast cancer with immunotherapy, according to the study.