Abstract IA17: New ways of targeting Ras

Abstract

Abstract Activating K-Ras mutations occur frequently in many cancers, and account for about one million cancer deaths per year worldwide. Currently, no therapies exist that target K-Ras directly, and K-Ras cancers are very difficult to treat. Indeed, they are excluded from treatment with targeted agents such as tarceva and vemurafenib. The K-Ras protein is a member of a large family of related proteins, of which H-Ras and N-Ras are the closest relatives. Ablation of all three Ras genes is likely to be toxic, as these proteins are essential in most signaling transduction pathways. We therefore need to target the mutant oncoprotein itself, or target K-Ras, without affecting H-Ras or N-Ras. The striking similarity of these proteins makes this task challenging, together with the fact that the K-Ras gene expresses two splice variants, K-Ras 4A and K-Ras 4B, each of which can contribute to cancer. Nevertheless, differences do exist between these proteins, and ways in which these can be exploited will be discussed. One approach takes advantage of unique properties of K-Ras 4B, the other targets an amino acid that is shared between K-Ras isoforms, but is not present in H-Ras or N-Ras, or other members of the Ras family. K-Ras processing can be prevented by compounds that block the CAAX box cysteine. We have identified compounds that interact covalently with this cysteine and block prenylation by farnesyl transferase or geranylgeranyl transferase. These compounds reduce expression of K-Ras in cells and have specificity for K-Ras relative to H-Ras and N-Ras and represent another approach to targeting K-Ras specifically. We have also used new biophysical methods to target K-Ras, including second harmonic generation. This method detects small allosteric changes in proteins, and thus allows identification of small molecules that bind to K-Ras at novel allosteric sites. Drug resistance is likely to be a problem with Ras inhibitors, as it is for all types of cancer therapies. We have identified an approach to killing drug resistant cells that appears effective against a wide range of resistance mechanisms. This was achieved by targeting persister cells that survive targeted agents, but have unique properties that make them vulnerable to attack. The implications of this new strategy will be discussed. Citation Format: Frank McCormick. New ways of targeting Ras [abstract]. In: Proceedings of the AACR International Conference: New Frontiers in Cancer Research; 2017 Jan 18-22; Cape Town, South Africa. Philadelphia (PA): AACR; Cancer Res 2017;77(22 Suppl):Abstract nr IA17.