Abstract 3009: Targeting MDM2-amplified tumors with AMG-232 to overcome drug resistance, inflammatory pro-tumorigenic cytokine production and hyperprogression with immune checkpoint therapy

Abstract

Abstract Mouse double minute 2 homolog (MDM2) is E3 ubiquitin-protein ligase which facilitates proteasomal degradation of p53. MDM2 amplification has been reported in different tumor types and recently been implicated as a potential marker for accelerated tumor growth or hyperprogression in various types of cancer after receiving immune checkpoint inhibitors. Thus, targeting MDM2 might be a promising treatment strategy in the era of cancer immunotherapy especially for tumor with MDM2 amplification or overexpression that may be predisposed to hyperprogression after exposure to immune checkpoint therapy. To investigate the potential of targeting MDM2 strategy, we explored the role of inhibition of MDM2 by AMG-232, an investigational oral selective MDM2 inhibitor. MDM2-amplified and MDM2-non-amplified ovarian clear cell carcinoma cell lines carrying p53 wild-type were treated with AMG-232 and showed a dose-dependent reduction in cancer cell viability. MDM2 amplification showed more resistance to the treatment with AMG-232. Consistent with previous data, treatment with AMG-232 led to activation of the p53 signaling pathway in cancer cells in a dose-dependent manner. Importantly, the effect of MDM2 inhibition on cytokines expression was tested and significant reduction in Interleukin-6 (IL-6), a proinflammatory cytokine which promotes tumorigenesis by multiple signaling pathways, was observed in a dose-dependent manner. Ongoing experiments are examining the role of targeting MDM2 using AMG-232 in combination with immunotherapy, including the impact on killing of MDM2-amplified ovarian cancer cells by T-cells in the presence of immune checkpoint therapy. Overall, our data suggest a potential therapeutic role of targeting MDM2 especially in tumors with overexpression or amplification of MDM2 to overcome drug resistance including hyperprogression in the context of immune checkpoint therapy. Citation Format: Ilyas Sahin, Shengliang Zhang, Lanlan Zhou, Don Dizon, Howard Safran, Wafik S. El-Deiry. Targeting MDM2-amplified tumors with AMG-232 to overcome drug resistance, inflammatory pro-tumorigenic cytokine production and hyperprogression with immune checkpoint therapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3009.