Abstract 5473: Towards a better understanding of MTH1 as a therapeutic target in RAS-driven cancer

Abstract

Abstract Oncogenic RAS signaling-generated reactive oxygen species (ROS) drive tumor progression by the hyperactivation of proliferative, anti-apoptotic, and metastatic pathways. Elevated ROS levels however can also cause oxidative DNA damage, leading to oncogene-induced senescence (OIS) and cell death. To avoid such tumor-suppressive outcomes, RAS-driven tumors often upregulate redox-protective proteins. The collective research from our group over the last few years has shown that oncogenic RAS elevates expression of the mammalian 8-oxo-dGTPase MutT Homolog 1 (MTH1), which in turn enables evasion of OIS, promotes transformation efficiency, and facilitates tumorigenicity. Our prior work has therefore demonstrated that MTH1 is beneficial to the spectrum of RAS-driven transformation, and that its shRNA-mediated targeting in oncogenic RAS-harboring lung cancer cells produces robust tumor-suppressive outcomes. However the first wave of chemical MTH1 inhibitors has led to controversial and conflicting results regarding MTH1 as a chemotherapeutic target. Here we evaluate the benefit of MTH1 inhibitors in wildtype. vs. oncogenic KRAS expressing cells, and directly assess the effects of oncogenic KRAS as well as three recently developed inhibitors on MTH1 8-oxo-dGTPase activity. Our results support that introduction of oncogenic KRAS elevates both MTH1 expression and activity, presumably through its elevation of ROS levels, and thus sensitizes cells to MTH1 inhibitors. The degree of this sensitization has a complex dependence on residual 8-oxodGTPase activity in the different cells following treatment with the MTH1 inhibitors, alternate antioxidant responses, and induction of different tumor suppressor pathways. Our data therefore highlight the importance of evaluating the molecular contexts and outcomes of MTH1 inhibition when determining its utility as a chemotherapeutic target. Citation Format: Govindi J. Samaranayake, Clara I. Troccoli, Mai Q. Huynh, Andrew Win, Debin Ji, Eric T. Kool, Priyamvada Rai. Towards a better understanding of MTH1 as a therapeutic target in RAS-driven cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5473. doi:10.1158/1538-7445.AM2017-5473