Abstract B020: Pan-RAS inhibitors to treat luminal B beast cancer

Abstract

Abstract The RAS oncoprotein has not traditionally been considered as an important driver of breast cancer due to the paucity of RAS mutations in this disease. However, RAS signaling pathways are frequently hyper-activated in breast cancers and genetic/epigenetic inactivation of RAS negative regulators (GAPs) is common. This is particularly true for Luminal B breast cancer. Luminal breast cancer makes up the majority of Breast Cancers, ~ 65% of cases. About 2/3 of these are classed as Luminal A and about 1/3 being the Luminal B class. Although current therapeutic options for luminal A (surgery, endocrine therapy) can be reasonably effective, Luminal B tumors are much more dangerous. These tumors are less sensitive to therapy in the first place and have a high frequency of relapse. Moreover, Luminal B tumors tend to occur more frequently in younger women and have a higher incidence of metastasis. One recent analysis has shown that Luminal B cancers have little better overall survival rates than the notorious triple negative breast cancers. Therefore, better therapies for Luminal B breast cancer are urgently required. One approach may be to target the hyper-active wild-type RAS oncoprotein that drives many of these Luminal B tumors. We have used in silico library screening followed by Medicinal Chemistry optimization to develop a series of novel small molecules that bind to all three main wild type RAS proteins and inhibit RAS function. We have validated the agents by using Microscale Thermophoresis binding procedures to quantify recombinant protein interaction. We used 3D growth inhibition and protein-based RAS signaling assays to quantify the biological action of the agents. Finally, we validated one of the more effective agents in vivo against a Luminal B cell line xenograft. This may be the first example of an effective anti-RAS therapy in breast cancer. It serves as proof of principal for the use of ant-RAS drugs in Luminal B disease. As basal breast cancers often exhibit loss of function of the RAS GAP called NF1, this strategy may have applications beyond Luminal B disease. Citation Format: Geoff Clark, Raphael Jigo, Howard Donninger, Joe Burlison, Mike Sabo, tariq Arshad, John Trent. Pan-RAS inhibitors to treat luminal B beast cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr B020.