Novel drug combo activates natural killer cell immunity to destroy cancer cells
When cancer drugs fail, a unique combination of already existing drugs could harness an under-targeted part of the immune system to join the fight
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. A new study led by Penn State College of Medicine scientists finds that another type of immune cell — natural killer cells — can be harnessed to pick up the slack when T cells no longer work and may also reinvigorate T cells to attack melanoma tumors. The team has identified a unique combination drug strategy to activate this natural killer cell-mediated immunity in mice. The individual agents are clinically used but not in combination, and the combination still must be demonstrated to be effective in humans.
“Long-term effective treatments are difficult to achieve in melanoma patients due to a variety of factors, one of which includes T-cell exhaustion. This occurs occurs over time as cancer patients are treated with drugs to enhance T-cell mediated immunity,” said Gavin Robertson, professor of pharmacology, pathology, dermatology and surgery. “If T-cell-mediated immunity is no longer working, switching to an approach that activates natural killer cell-mediated immunity could be a major advancement.”
Robertson explained that natural killer cells can be lacking in solid tumors, likely due to limitations of signals attracting them into tumors, activation once in the tumor and the general immunosuppressive microenvironment that occurs in tumors. He said that therapies that can increase natural killer cell infiltration and/or activation in tumors are urgently needed.
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.
“Emerging evidence suggests that restoration of p53 signaling within tumor cells can lead to natural killer cell infiltration and activation in the tumor,” said Robertson, a Penn State Cancer Institute researcher. “Yet, studies have found that drugs targeting MDM proteins in order to restore p53’s tumor-suppression activities tend to be toxic.”
Instead, he said, targeting a different set of proteins — AKT and WEE1 — may be a potentially non-toxic and novel approach to increase p53 activity. Like MDM proteins, explained Robertson, both AKT and WEE1 are overexpressed in 80% of melanomas and play a unique role with the MDM proteins to prevent the p53 pathways from being active. What they found is that targeting both AKT and WEE1 uniquely reverses the effects of the MDM proteins, reactivating the p53 pathways in a way that does not occur when using MDM inhibitors. Thus, the effect is better p53 pathway activation without the toxic effects seen with MDM inhibitors.
In their study, which published on June 3 in the journal Cancer Immunology Research, Robertson and his colleagues 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. The team incubated the cells, along with different concentrations of the two drugs, for 24 hours. Afterward, they added natural killer cells and later assessed the number of healthy melanoma cells that remained.
“We 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,” said Robertson. By contrast, he added, inhibiting the proteins individually was not effective at causing the natural killer cell response.
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Other College of Medicine authors on the paper include Saketh Dinavahi, senior research scientist; Yu-chi Chen, senior research scientist; Kishore Punnath, postdoctoral researcher; and Arthur Berg, associate professor of public health sciences. Dinavahi reports grants from Melanoma Research Foundation during the conduct of the study. Robertson reports a patent for US2018/0325902A1 pending and issued.
The Foreman Foundation for Melanoma Research, the Mike Geltrude Foundation, the Chocolate Tour Cancer Research Fund, the Melanoma Research Alliance, the National Cancer Institute of the National Institutes of Health, the Melanoma Research Foundation and the National Health and Medical Research Council of Australia supported this research. The content is solely the responsibility of the authors and does not necessarily represent the official views of the funders.
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