(HealthDay News) — Pevonedistat, a specific inhibitor of the NEDD8 activating enzyme, inhibits the activity of cullin E3 ligases, inhibiting cancer cells in vitro, according to a study published in the August issue of EBioMedicine.
Noting that the cullin-based CRL4-CDT2 ubiquitin ligase regulates cell proliferation, and that CDT2 is overexpressed in cutaneous melanoma and predicts poor survival, Mouadh Benamar, from the University of Virginia in Charlottesville, and colleagues examined the role of pevonedistat in cutaneous melanoma.
The researchers found that pevonedistat inhibited activity of cullin E3 ligases, resulting in cancer cell inhibition in vitro and suppression of tumor in nude mice. Pevonedistat was effective for inhibiting proliferation of melanoma cell lines in vitro via induction of rereplication-dependent permanent growth arrest and through a transient mechanism not dependent on rereplication. Heterozygous deletion of CDKN1A (encoding p21) or SET8 in melanoma cells showed that rereplication-mediated cytotoxicity of pevonedistat was mediated via prevention of the degradation of p21 and SET8 and was necessary for suppression of melanoma in nude mice. Pevonedistat-induced transient growth suppression was independent of p21 or SET8, and was not sufficient for inhibition of in vitro tumor growth. Pevonedistat also synergized with PLX4720 to inhibit BRAF melanoma, and suppressed PLX4720-resistant melanoma cells.
“These findings demonstrate that the CRL4-CDT2-SET8/p21 degradation axis is the primary target of inhibition by pevonedistat in melanoma and suggest that a broad patient population may benefit from pevonedistat therapy,” the authors write.
The authors have filed two patent applications related to this work.