Abstract 4448: Effects of adagrasib on cholesterol, lipid and glucose gene expression regulation in tumor xenograft models and patient samples

Abstract Introduction: Clinically active KRASG12C inhibitors have represented a key research breakthrough and led to novel treatment options for lung, colorectal and other cancer patients harboring this mutation. While treatment with KRASG12C inhibitors are clinically active in the majority of patients, the depth and duration of response is variable and most patients ultimately progress. This variation in therapeutic response highlights the need for a better understanding of drug mechanism of action and the identification of rational combination strategies. Oncogenic KRAS mutations hyperactivate the MAPK pathway, create an immunosuppressive tumor microenvironment, and promote glycolysis even in the presence of oxygen commonly known as the Warburg effect. This altered metabolic state is marked by increased glucose uptake and lactate production, providing necessary substrates for rapid tumor growth. Results: Pharmacological inhibition of KRASG12C with a potent and selective KRASG12C inhibitor, adagrasib, revealed marked alterations of metabolic gene expression programs in tumor samples collected from mouse xenograft studies and repeat biopsies provided by patients enrolled on adagrasib clinical trials. Upregulation of genes involved in reverse cholesterol transport including ApoE, NR1H3 (LXRa) and ABCA1 was observed across both preclinical tumor xenografts and patient samples following adagrasib treatment. Additionally, decreased expression of Glut1 and low-density lipoprotein receptor (LDLR) genes were also observed in both tumor models and patients suggesting that adagrasib treatment results in an extensive shift in uptake and utilization of cholesterol, lipid, and glucose. The impact of adagrasib treatment on circulating metabolic parameters in tumor xenograft-bearing mice were investigated in follow up studies. Conclusions: Taken together, these data suggest adagrasib modulates cholesterol efflux, glucose and lipid pathways and alters tumor and systemic metabolic regulation. Additional research may yield a targetable collateral vulnerability and rational combinatorial strategy. Citation Format: Fabiola Shelton, Natalie Hoffman, David Trinh, Xousaen M. Helu, Andrew Calinisan, Allan Hebbert, Larry Yan, David M. Briere, Laura Hover, Julio Fernandez-Benet, Kenna Anderes, James G. Christensen, Jill Hallin, Peter Olson. Effects of adagrasib on cholesterol, lipid and glucose gene expression regulation in tumor xenograft models and patient samples [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4448.