Stopping cancer cells by blocking a growth-promoting protein and reactivating protective p53

The process of cell growth and division is controlled by genes. When this normal process goes awry, cells can grow out of control, forming cancer and producing new proteins that continue to feed the disease. Scientists at Karolinska Institutet in Sweden have zeroed in on one of those proteins, eIF4A3, and found a way to block it. They believe the discovery could inspire the development of new cancer treatments.

The team used a small molecule to bring the overproduction of eIF4A3 in cancer cells under control. That prompted changes in the cancer cells that caused them to stop dividing and, ultimately, to die, they reported in the journal Science Advances.

One immediate result of blocking eIF4A3 was that it activated p53, a protein that’s well known for its ability to protect against cancer by preventing DNA-damaged cells from replicating. Another protein, MDM2, often prevents p53 from operating normally in cancer cells—a problem the elF4A3 blocker seemed to address, the Swedish team reported.

“Interestingly, we noted that the blocking eIF4A3 also meant that the MDM2 protein changed. This change helps to maintain and strengthen p53 and can be beneficial when we want to inhibit the growth of cancer cells,” said first author Dimitris Kanellis, a postdoctoral fellow at Karolinska Institutet, in a statement.

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The discovery comes one month after a related finding from another Karolinska Institutet team. Those researchers reported that inhibiting MDM2 with a drug developed by Aileron Therapeutics could reactivate p53 in mouse models of immunotherapy-resistant melanoma. Aileron recently launched an early trial of the drug in patients with p53-mutated non-small cell lung cancer.

In the new study, the Karolinska Institutet researchers found that depleting eIF4A3 changed protein production in cancer cells by disrupting a process called ribosome biogenesis. That insight could help select patients most likely to respond to eIF4A3 inhibition, the researchers suggested.

For example, colon tumors often grow quickly and express high levels of ribosomes, while some sarcomas overproduce MDM2.

In fact, the researchers believe there may be synergies between cancer drugs that are already in use and eIF4A3 blockers—a hunch they are now planning to research further, they said.