Abstract 2786: Targeting oncogene and inflammation for cancer therapy

Abstract Accumulating evidence has demonstrated that the overexpression of and the loss of tumor suppressor genes contribute to the aggressiveness, poor prognosis, and poor response to treatment associated with advanced cancer. Overexpression and activation of the MDM2 and NFAT1 oncogenes frequently occur in human cancer and is associated with invasive and high grade/late-stage tumors, metastasis, and recurrence, and are negative prognostic factors for cancer patients. Dual targeting MDM2 and NFAT1 represents a novel molecular target for the treatment of cancer. However, most of the current MDM2 inhibitors have been designed to block the binding between MDM2 and p53, and have limited efficacy against tumors with mutant or deficient p53. Considering that high incidence of TP53 mutations and MDM2 overexpression in tumors, these MDM2 SMIs are expected to have low or no efficacy against those types of cancer. Therefore, there is an urgent need to identify a novel, p53-independent strategy to inhibit MDM2, in order to affirm the therapeutic value of targeting MDM2. In addition, as an important inflammatory factor, there are no specific NFAT1 inhibitors developed for cancer therapy. By employing crystallization screening, NMR-based screening, and high-throughput virtual and cell-based screening assays, we discovered a class of makaluvamine analogs with the desired property. One of these analogs, MA242, was identified as a potent and selective MDM2 and NFAT1 inhibitor. Its in vitro and in vivo anti-breast cancer activities and underlying mechanisms of action were evaluated in breast cancer cell lines with various p53 backgrounds. Our results demonstrated that MA242 directly bound to MDM2 and NFAT1 protein with high affinity and induced its protein degradation. As a result of this binding, MA242 decreased cell proliferation, and induced apoptosis and G2/M phase arrest in breast cancer cell lines, regardless of the p53 status. Furthermore, MA242 inhibited the tumor growth and metastasis in orthotopic and patient-derived xenograft (PDX) models, without any host toxicity. Single-cell sequencing results provided the molecular and cellular crosstalk between cancer and immune system, and identified the predictive biomarkers of response after the treatment. In conclusion, MA242 is a potent and selective MDM2 and NFAT1 dual inhibitor with distinct mechanisms of action compared to the existing inhibitors. Our data suggest that the dual targeting oncogene and inflammation is a promising strategy for the treatment of human cancer. (Supported by NIH R01CA214019 and a UH DDI Seed Grant.) Citation Format: Wei Wang, Sayantap Datta, Sadanandan E. Velu, Ming Luo, Ruiwen Zhang. Targeting oncogene and inflammation for cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2786.