Abstract C134: The MDM2 degrader KTX-049 is highly potent in TP53 wild-type (p53 WT) Merkel cell carcinoma (MCC)

Abstract

Abstract Background and aims: MCC is a highly aggressive neuroendocrine carcinoma of the skin with a high fatality rate. Clonal integration of Merkel cell polyomavirus (MCPyV) occurs in about 80% of all MCCs. These virus positive MCC (MCCP) tumors have a low tumor mutational burden and usually express wild type (WT) p53 (TP53). In contrast, virus negative MCC (MCCN) tumors present a predominantly UV mutational signature, a high mutational burden and often have alterations in p53. MCCP tumors express MCyV small T antigen (ST) and a truncated form of large T antigen (LT). The MCyV ST in MCCP tumors, recruits MYCL and EP400 to form the SLaP complex that specifically trans-activates several genes. A direct target of the SLaP complex is MDM2, an E3 ubiquitin ligase of p53 that inhibits p53-mediated tumor suppression. The use of MDM2 inhibitors can stabilize p53 in p53 WT tumors. However, currently, no MDM2 inhibitors are approved for treatment of MCC. Furthermore, MDM2 degraders have not been studied in the context of MCC. Here, we aim to analyze the efficacy of KTX-049, a potent MDM2 degrader, in MCC and compare its efficacy to the previously reported and highly potent MDM2 inhibitor, DS-3032. Experimental procedures: Established MCCP cell lines with functional p53, non-functional p53 and two p53 WT MCCP patient derived cell lines (PDCLs) were treated with KTX-049 or DS-3032 and the effect on cell viability was analyzed using a luminescence-based assay. Apoptosis induction was studied using the caspase 3-7 Glo assay. The p53 response in MCC cells post KTX-049 or DS-3032 treatment was assessed by western blot (WB) analysis of p53 and its downstream effectors. Results: KTX-049 and DS-3032 reduced cell viability of p53 WT MCCP cell lines but not cell lines with non-functional p53. Notably, all sensitive cell lines had ≥100-fold lower absolute IC50 values for KTX-049 as compared to DS-3032. Additionally, KTX-049 effectively reduced cell viability of the sensitive cell lines even after brief exposures. KTX-049 also triggered a rapid and sustained p53 response and apoptosis induction in p53 WT MCC cells. Conclusions: KTX-049 is a promising MDM2 degrader effective against p53 WT MCC cell lines. These results provide evidence for in vivo exploration of KTX-049 in models of MCC. Citation Format: Varsha Ananthapadmanabhan, Yogesh Chutake, Jessica Filiatrault, Stefanie Schalm, Alice McDonald, James A DeCaprio. The MDM2 degrader KTX-049 is highly potent in TP53 wild-type (p53 WT) Merkel cell carcinoma (MCC) [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C134.