Kdo6 Is A Novel Anti-Cancer Drug That Causes Cell Death In Triple-Negative Breast Cancer Cell Lines And Tumor Xenografts

Proceedings: AACR 107th Annual Meeting 2016; April 16-20, 2016; New Orleans, LADevelopment and screening of small molecule compounds for anti-cancer activity has been of prime interest to the scientific community following the success of targeted, large anti-cancer molecules such as therapeutic antibodies. Small molecules pass more easily through cell membranes and may cross the blood-brain barrier. KD06 is a small molecule triptan-like compound whose parent molecule binds and inhibits serotonin receptors. This compound increases apoptosis of the triple-negative breast cancer cell lines MDA-MB-231 and MDA-MB-157 via caspase activation. Treatment with KD06 also causes increased autophagy as well as activation of ER stress responses. The growth of tumor xenografts of MDA-MB-231 cells in nude mice are significantly inhibited by twice weekly treatment with 30mg/kg KD06. Analysis of signaling changes by KD06 using reverse phase protein array (RPPA) revealed significant decreases in Akt/mTOR signaling leading to decreased activation of the translation initiation factor 4E-BP1. Other notable changes included decreased expression of proteins important for mitosis such as Cyclin B1, Aurora B and PLK1, and increased phosphorylation of EGFR and increased expression of PDGFR. Analysis of PIP3 and ATP levels showed no change after treatment with KD06, indicating that decreased signaling through Akt/mTOR is not likely due to PI3K inhibition or AMPK activation. Immunofluorescence with KD06 treated cells revealed a change in cell shape after 4 hours of treatment that was reminiscent of cells treated with microtubule binding drugs. Akt localization was affected. These results imply that KD06 may have anti-cancer activity through its effect on microtubule dynamics, inhibiting proper localization and signaling of molecules important for survival and protein translation such as Akt and mTOR.Citation Format: Nancy D. Ebelt, Clint D J Taveres, Xuemei Xie, Youssef W. Naguib, Jiney Jose, Tinashe B. Ruwona, Ashwini K. Devkota, Jihyun Park, Tamer S. Kaoud, Eric V. Anslyn, Jeffrey T. Chang, Zhengrong Cui, Chandra Bartholomeusz, Kevin N. Dalby. KD06 is a novel anti-cancer drug that causes cell death in triple-negative breast cancer cell lines and tumor xenografts. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3774.