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Scientists Identify Potential Drug Combination to Eliminate Cancer with ‘Killer Cells

Scientists Identify Potential Drug Combination to Eliminate Cancer with ‘Killer Cells

Saturday, 18 June, 2022 - 08:00
A researcher works in a lab run by Moderna Inc. (Reuters)

Most skin cancer drugs that activate the immune system work by triggering immune cells, called T-cells, to attack tumors, but when T-cells are activated for too long, they can wear out and cease to function.

In a new study led by Penn State College of Medicine, scientists found that another type of immune cell — natural killer cells — can be harnessed to pick up the slack when T-cells no longer work.

The team has identified a unique combination drug strategy to activate this natural killer cell-mediated immunity in animals, and still must be demonstrated to be effective in humans.

Known as “the guardian of the genome,” p53 is a class of proteins tasked with suppressing tumor development. However, melanoma cells counter this attack by producing Murine Double Minute (MDM) proteins, which hamper the activity of p53 and prevent the pathway from being active.

Former studies tried to restore the p53 signaling within tumor cells with drugs that target the MDM protein, which can lead to natural killer cell infiltration and activation in the tumor. Yet, they found that these drugs tend to be toxic.

In the new study, published in the latest issue of the journal Cancer Immunology Research, the researchers said two other proteins, AKT and WEE1 work with MDM to inhibit the activity of “the guardian of the genome” calling natural killer cells.

They determined a potentially non-toxic and novel approach to target those two proteins, which are overexpressed in 80% of melanomas. What they found is that targeting both AKT and WEE1 reactivates the p53 pathways in a way that does not occur when using MDM inhibitors.

In their study, the team tested the abilities of two AstraZeneca cancer drugs — capivasertib (AZD5363), which is known to inhibit AKT, and adavosertib (MK1775), which is known to inhibit WEE1 — to solicit a natural killer cell immune response.

They conducted their first experiment with cultured mouse melanoma cells and living sick mice. They found that simultaneous inhibition of both AKT and WEE1 with capivasertib and adavosertib synergistically reduced melanoma cell proliferation and increased melanoma cell death mediated by the natural killer cells.

“When we used these drugs to draw natural killer cells into the tumors, the natural killer cells also pulled in T-cells, whose activity could then be triggered with an additional agent, called an immune checkpoint inhibitor. Using this approach, we were able to completely eliminate tumors in mice,” said Gavin Robertson, professor of pharmacology, pathology, dermatology and surgery, Penn State College of Medicine.

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