Abstract PL04-04: Synthetic lethal approaches to targeting Ras mutant cancers.

Abstract

Abstract The RAS oncogenes are very frequently activated by mutation in human tumors, which very often show continued dependency on the signaling functions of RAS. In addition to controlling the RAF/MEK/ERK pathway, RAS proteins are established to be important direct regulators of type I phosphoinositide 3-kinases (PI3Ks), interacting via an amino terminal RAS binding domain (RBD). Disruption of PI3K p110alpha activation by oncogenic KRAS has been shown to prevent tumor development in a mouse model of lung cancer. Disruption of RAS-PI3K p110alpha interaction in established lung tumors prevents tumor progression and results in long-term stabilization of lung tumors. Coordinate inhibition of the MAPK pathway at the same time promotes tumor regression and dramatically reduces tumor burden. However, as yet it is unclear whether the combined targeting of pathways that RAS controls, such as RAF/ERK and PI 3-kinase/AKT, will prove effective in the treatment of RAS mutant cancers in the clinic, or whether this approach will prove unacceptably toxic. It is therefore important that other means of targeting this critical oncogene are considered. One such approach is the development of agents that directly inhibit the function of RAS proteins, for example by blocking interaction with effectors. Another approach, which will be explored here, is the identification of unique dependencies of RAS mutant tumor cells through the use of functional genomic screens. We have used RNA interference libraries on a panel of lung cancer cell lines to determine genes that are required for the survival of cells with oncogenic KRAS mutations, but not wild type KRAS. This has led to the identification of signaling networks that are essential for RAS mutant cells, including a transcriptional programme controlled by the GATA2 transcription factor. In mouse models of lung cancer, deletion of GATA2 leads to dramatic regression of RAS induced tumors. Although GATA2 itself is likely to be undruggable, investigation of the transcriptional targets of GATA2 has revealed three key pathways that are much more tractable: the proteasome, NF-kB and Rho signaling. Combined suppression of GATA2 regulated pathways with clinically approved inhibitors of the proteasome and Rho kinase causes marked tumor clearance. Discovery of the non-oncogene addiction of KRAS mutant lung cancers to GATA2 function presents a network of druggable pathways for therapeutic exploitation. We are currently testing combinations of GATA2 functional targeting with other approaches that show potential, such as MEK plus PI 3-kinase inhibition, and immune checkpoint modulators. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):PL04-04. Citation Format: Julian Downward. Synthetic lethal approaches to targeting Ras mutant cancers. [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 PL04-04.