Scientists have identified a protein that plays a key role in the action of several emerging cancer therapies, reporting their findings in the journal Cancer Research. Most cancer drugs cause cancer cells to shrivel and die in a controlled process known as apoptosis. But apoptosis usually doesn’t activate immune cells strongly. The identified protein, a sodium ion channel known as TRPM4, is critical to cancer therapies that promote this type of cell death, called necrosis. Unlike apoptosis, necrosis strongly signals the immune system to target and clean up the remains of dying cells. This suggests that treatments that promote necrosis may improve immunotherapies against solid tumors. TRPM4 is the first protein mediator of anticancer therapy-induced necrosis to be described.
In previous work, Dr. Shapiro, professor of chemistry and study co-author Paul Hergenrother and their colleagues developed two drugs — a compound called BHPI and later a more effective agent known as ErSO — that stimulate necrosis in solid tumors, shrinking drastically and often eradicate primary and metastatic tumors in mice. These drugs work by binding to estrogen receptors on cancer cells and pushing a normally protective cellular stress response pathway to its extremes. This pathway, the “anticipatory unfolded protein response, or a-UPR,” ultimately causes the cell to swell, leak, and die. To identify the relevant proteins, Shapiro and his colleagues examined breast cancer cells by knocking out each of the approximately 20,000 individual genes in the cancer cells and then treating the altered cells with BHPI or ErSO.
Cells that resisted treatments with these agents revealed which genes were essential for the drugs to be effective. The researchers were surprised to find that TRPM4 emerged as a key factor in the necrosis process in ErSO and BHPI-treated cancer cells. The team also found that TRPM4 was important for the activity of several other necrosis-inducing anticancer therapies. Further studies revealed that an ErSO-induced increase in intracellular calcium causes the TRPM4 channel to open, allowing sodium ions and water to flow into the cell. The influx causes the cell to swell, rupture and leak, activating the immune cells and causing them to rush to the site of the dead cells. By targeting the TRPM4 pathway in solid tumours, scientists can further improve the necrosis-inducing cancer therapies available to fight such tumours.
Here’s how Dr. Shapiro commented on the implications of the finding: “This will allow physicians to identify patients who are most likely to benefit from necrosis-inducing therapies because their tumors have high levels of TRPM4. Cancer treatment has been transformed by immunotherapy, which puts the brakes on immune cells, allowing them to attack cancer cells. But immunotherapy has had limited success against solid tumors such as ER-positive breast cancer and pancreatic cancer. We have discovered that the anticancer drug ErSO acts like the starter of a car which, once started, is no longer needed. It is the cellular swelling caused by TRPM4 that drives the lethal stress that kills cancer cells. Just one hour of exposure to ErSO actually killed the cancer cells days later.”
By Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
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Scientific publications
Ghosh S et al. Cancer Res. 2023 Jul 31:OF1-OF16.
WangJ et al. Front Mol Biosci. 2022 Aug 23; 9:985434.
Kappel S et al. Cell Calcium. 2022 June; 104:102591.