Abstract A032: Targeting RAS beyond KRAS, a review

Abstract

Abstract RAS proteins belong to the family of GTPases and plays instrumental role in cellular growth and proliferation and dysregulation of RAS signalling is one of the key drivers of tumorigenesis. The RAS protein has four isoforms namely KRAS4A, KRAS4B, NRAS and HRAS with amino acid codons 12, 13 and 61 as common hotspots for RAS mutations. Each of these hotspot mutations appears across several cancer types, however each of them have been noted to have specific distribution across different tissues. For example, mutations in codon 12 of KRAS are most common in pancreatic, lung and colorectal cancer, NRAS mutations affecting Q61 and G12 are most prevalent in melanoma and haematological malignancies, respectively, and HRAS mutations are more frequently altered in thyroid, bladder and head and neck cancers. Substantial efforts have been made to develop small molecule inhibitors targeting KRASG12C, with demonstrated success in clinic. Early success with KRASG12C has prompted researchers targeting other RAS isoforms, such as H-RAS and N-RAS to address RAS mutated cancer burden. Discovery of pan-RAS monobody that binds to all RAS isoforms have opened new opportunities. Development of small molecule inhibitors of RAS membrane association is gaining potential as a therapeutic strategy to curb RAS signalling; Lonafarnib and Tipifarnib, inhibitors of farnesyltransferase that lipidate Ras to facilitate membrane localization, have shown effectiveness in HRAS mutated cancers and are in active clinical evaluation. Although the lack of a hydrophobic binding pocket in NRAS poses challenges to drug targeting, specific strategies such as amphiphile-mediated depalmitoylation to target the post-translational modification of NRAS and reduce its activity are being investigated. The wide variety of approaches to target the RAS signalling pathway, beyond KRAS, have resulted in a broadening patent landscape. While finding ways to specifically target RAS mutants remains a daunting challenge, herculean efforts to make clinically useful RAS-targeted drugs are beginning to provide a bounty of weapons to fight against RAS-driven tumors. Citation Format: Neetu Singh, Darren R. Tyson, Partha Pratim Sarma, Sathish Katike, Prashant K. Bhavar, Uday Kumar Surampudi. Targeting RAS beyond KRAS, a review [abstract]. In: Proceedings of the AACR Special Conference: Targeting RAS; 2023 Mar 5-8; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Res 2023;21(5_Suppl):Abstract nr A032.