Milademetan is a highly potent MDM2 inhibitor in Merkel cell carcinoma
August 16, 2022
August 16, 2022
The basis for the activity in Merkel cell carcinoma of an oral ‘MDM2 inhibitor’, milademetan (Rain Therapeutics), is nicely explained in this study. For this therapy to work, the p53 protein (the ‘guardian of the genome’) must not have been directly mutated in the MCC tumor cells, meaning p53 would still be capable of functioning. Indeed, MCC that was caused by the Merkel polyomavirus, p53 has typically not been directly damaged, and after its levels go up (milademetan inhibits the MDM2 protein that normally destroys the p53 protein) p53 can then go on to cause MCC tumor cells to kill themselves. At the 2022 ASCO meeting, an early report on a clinical trial of a related MDM2 inhibitor (navtemadlin, or KRT-232, by Kartos) clearly showed that this approach can benefit some MCC patients, even if they have MCC that is not responding to checkpoint immune therapy.
Merkel cell carcinoma (MCC) is an aggressive neuroendocrine carcinoma of the skin with 2 etiologies. Merkel cell polyomavirus (MCPyV) integration is present in about 80% of all MCC. Virus-positive MCC (MCCP) tumors have few somatic mutations and usually express WT p53 (TP53). By contrast, virus-negative MCC (MCCN) tumors present with a high tumor mutational burden and predominantly UV mutational signature. MCCN tumors typically contain mutated TP53. MCCP tumors express 2 viral proteins: MCPyV small T antigen and a truncated form of large T antigen. MCPyV ST specifically activates expression of MDM2, an E3 ubiquitin ligase of p53, to inhibit p53-mediated tumor suppression. In this study, we assessed the efficacy of milademetan, a potent, selective, and orally available MDM2 inhibitor in several MCC models. Milademetan reduced cell viability of WT p53 MCC cell lines and triggered a rapid and sustained p53 response. Milademetan showed a dose-dependent inhibition of tumor growth in MKL-1 xenograft and patient-derived xenograft models. Here, along with preclinical data for the efficacy of milademetan in WT p53 MCC tumors, we report several in vitro and in vivo models useful for future MCC studies.