Abstract SY25-02: Synthetic lethal approaches to targeting RAS mutant tumors: Is there an Achilles' heel.

Abstract

Abstract The RAS oncogene is frequently activated by mutation in human tumors, including most pancreatic cancers and many lung and colon cancers, which very often show continued dependency on its signaling functions. RAS proteins are established to be important direct regulators of p110alpha and p110gamma 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. 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 investigating the ability of these targeting strategies to impact on RAS induced cancer formation in other common RAS driven cancer models. The ability of targeting GATA2 function to cause regression of KRAS mutant lung cancers with loss of p53 function has also been established in mouse models, suggesting that this approach may be viable in more advance tumors. Future challenges will include how to convert the major regressions that are seen when targeting GATA2 in mouse models of lung cancer into lasting clearance of the disease. In order to do this we are testing combinations of GATA2 functional targeting with other approaches that show potential, such as MEK plus PI 3-kinase inhibition. A major limitation to the efficacy of these approaches is likely to be the evolution of drug resistance, so mechanisms whereby this can occur are being actively investigated, both for the synthetic lethal hits and also the RAS signaling pathway inhibitors. Citation Format: Julian Downward. Synthetic lethal approaches to targeting RAS mutant tumors: Is there an Achilles' heel. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr SY25-02. doi:10.1158/1538-7445.AM2013-SY25-02