Pevonedistat May Pack a Powerful Punch Against Melanoma

Researchers from the University of Virginia Cancer Center are now reporting that the experimental agent pevonedistat may be able to combat melanoma in whole new way. They recently published a study in EBioMedicine suggesting that this agent may be highly effective in treating all forms of melanoma, and even may be a promising second-line agent in melanoma patients who become resistant to first-line therapy.

“We have great hope that this drug will have very significant impact on melanoma in general,” said study investigator Tarek Abbas, PhD, who is with the Department of Radiation Oncology at the University of Virginia, in a news release. “In fact, the drug is very effective on all melanomas, including those for which an effective therapeutic is lacking.”

The CDT2 gene, a substrate receptor for the CRL4 ubiquitin ligase, may be a prognostic marker and therapeutic target in melanoma. They report that CDT2 is required for melanoma cell proliferation and inhibition of CRL4CDT2. The Virginia researchers have demonstrated that pevonedistat is able to suppress melanoma in vitro and in vivo through the induction of DNA rereplication and senescence through the stabilization of the CRL4CDT2 substrates p21 and SET8.

Pevonedistat, which already is in clinical trials, may be able to help combat other forms of cancer as well.  Abbas said until now it was uncertain how the drug worked. However, it now appears that certain tumors “are addicted” to this gene. The researchers have found that CDT2 is not likely to function as a classical oncogene. Instead, they report that it may act as a cancer-associated gene. This theory is supported by the finding that CRL4CDT2 inactivation by this agent induces rereplication in melanoma cells. However, pevonedistat failed to do so in noncancer melanocytic cells.

Abbas and colleagues have shown that melanoma cells, which have higher levels of expression of CDT2, are much more susceptible to the drug. High levels of the CDT2 protein are found in many other tumors, including brain, breast, and liver tumors.

The safety and effectiveness of pevonedistat is still being investigated. However, researchers are optimistic it will have a very significant impact on melanoma in general. Abbas said it is very promising that the drug appears to be very effective on all melanomas, including those for which effective therapeutic approaches are nonexistent.

The investigators reported that pevonedistat additionally is synergized with the BRAF kinase inhibitor PLX4720 to inhibit BRAF melanoma. They also found that pevonedistat is able to suppress PLX4720-resistant melanoma cells. Additionally, pevonedistat synergizes with vemurafenib (Zelboraf) in vivo and suppresses vemurafenib-resistant melanoma cells, according to the published report.