Abstract B66: A novel cre-versible approach for identifying synthetic lethal interactions in the DNA damage response in vivo.

Abstract

Abstract A fundamental limitation in the ability to devise new therapeutic strategies for manipulating the DNA damage response to treat cancer is the identification of synthetic lethal interactions that function in tumors in vivo. We recently identified the stress activated p38MAPK/MK2 pathway as a critical component of the DNA damage response network in tumor cells in vitro. When treated with genotoxic chemotherapy, MK2 is essential for the survival of tumor cell lines that lack functional p53, but is dispensable in p53-proficient cells. A critical function of MK2 in p53-deficient cells is the post-transcriptional regulation of gene expression, namely the stabilization of the mRNA of cell cycle regulators such as Gadd45α. Intriguingly, MK2 also plays an essential role in the biosynthesis of inflammatory cytokines, including IL-1, IL-6 and TNFα that are key signaling components in the tumor microenvironment. These MK2-regulated cytokines are likely to play important roles in promoting tumor development, as many cancers arise in setting of chronic inflammation, as well as in the creation of chemo-resistant niches where therapeutic resistance develops. The fact that p53 is commonly lost in tumors suggests that the therapeutic targeting of MK2 may be a useful strategy to enhance destruction of tumors by genotoxic chemotherapy. To explore the role of the p38MAPK/MK2 pathway in the integration of the DNA damage response and cytokine signaling during tumor development and chemotherapeutic response in vivo, we have generated a novel mouse model in which Cre-mediated recombination can be used to create MK2-proficient and deficient tumors within a single animal. This strategy allows direct comparison of MK2 synthetic lethality with genetic mutations that promote tumor development and with the tumor response to DNA damaging chemotherapy in a novel internally controlled setting in vivo. Furthermore, this approach potentially allows tumor autonomous signaling events after DNA damage to be distinguished from signaling events within the stromal microenvironment. Using this approach in a murine autochthonous model of non-small-cell lung cancer (NSCLC) we demonstrate that synthetic lethality between p53 and MK2 can successfully be exploited for enhanced chemo-sensitization of tumors to DNA damaging chemotherapy in vivo. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B66. Citation Format: Sandra Morandell, H.-Christian Reinhardt, Ian G. Cannell, Michael B. Yaffe. A novel cre-versible approach for identifying synthetic lethal interactions in the DNA damage response in vivo. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B66.