Galectin-3, A Target For Kras-Addicted Lung Cancer

KRAS-mutant cancers are notoriously therapy-resistant. While responsible for oncogenesis, mutant KRAS or the sustained activation of KRAS-driven effectors may or may not be required throughout the course of cancer progression. Thus, understanding which tumors remain dependent on oncogenic KRAS could lead to the identification of unique vulnerabilities and opportunities to treat them. We previously discovered that the carbohydrate-binding Galectin-3 (Gal-3) brings together KRAS with integrin αvβ3 at the cell membrane in epithelial cancer cells to promote tumor progression. Here, we show that by directly binding to the cell surface receptor integrin αvβ3, Gal-3 drives addiction to oncogenic KRAS by enhancing macropinocytosis and reducing mitochondrial reactive oxygen species (ROS). This pathway drives increased expression of SOD2, a superoxide dismutase that clears mitochondrial ROS to protect against cell death. Targeting Gal-3 with a clinically active drug decreases macropinocytosis and increases ROS to eradicate KRAS-addicted lung cancer in patient-derived xenografts and spontaneous KRAS-driven lung cancer in mice. Our work reveals Gal-3 as a druggable target for KRAS-addicted lung cancer, and indicates integrin αvβ3 as a biomarker to identify this dependence. Citation Format: Laetitia Seguin, Maria F. Camargo, Hiromi I. Wettersten, Shumei Kato, Tami von Schalscha, Kathryn C. Elliott, Sara M. Weis, David A. Cheresh. Galectin-3, a target for KRAS-addicted lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3067. doi:10.1158/1538-7445.AM2017-3067