Abstract PR03: Selective sensitization of mutant K-Ras cancer cells to DNA damage based therapies by targeting wild type H- and N-Ras.

Abstract

Abstract Mutations in Kras are highly prevalent in human cancers and are strongly predictive of resistance to chemotherapy. As the constitutive activation of K-Ras has been believed to confer functional autonomy and dominance over the wild type Ras forms, it has been thought that wild type Ras forms are dispensable to the mutant K-Ras driven tumorigenic phenotype. Here we demonstrate a functional dependence of mutant K-Ras driven tumors on wild type Ras for the activation of the DNA damage response, and that this dependence can be exploited to specifically sensitize K-Ras cancers to DNA[[Unable to Display Character: –]]damage-inducing agents. We show that in mutant K-Ras cancer cells, wild type H-Ras and N-Ras are required for the activation of Chk1, the G2 DNA damage checkpoint, and the cellular response to DNA-damage-inducing chemotherapy. Specifically, we show that targeted depletion of wild type H- and N-Ras in mutant K-Ras cancer cells leads to the hyperactivation of the Erk/p90RSK and PI3K/Akt pathways, and as a consequence, the phosphorylation of Chk1 at an inhibitory site, Ser 280. The resulting inhibition of ATR/Chk1 signaling abrogates the activation of the G2 DNA damage checkpoint, and confers a specific sensitization of mutant K-Ras cancer cells to DNA damage therapeutic agents both in vitro and in vivo. Our results demonstrate a previously unappreciated role for wild type Ras in the DNA damage response of mutant K-Ras cancer cells and reveal a promising approach for targeting K-Ras-driven tumors. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):PR03. Citation Format: Elda Grabocka, Yuliya Pylayeva-Gupta, Eyoel Yemanaberhan, Veronica Lubkov, Laura Taylor, Dafna Bar-Sagi. Selective sensitization of mutant K-Ras cancer cells to DNA damage based therapies by targeting wild type H- and N-Ras. [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 PR03.