Abstract 1869: Dislodgement of K-Ras from plasma membranes, induction of apoptosis and tumor regression by PCAIs, a novel class of polyisoprenylated small molecules

Abstract

Abstract Although mutation-induced dysregulation of Ras signaling constitutes the biochemical change that drives some of the most difficult-to-manage cancers, directly targeting the constitutively active mutant Ras GTPases has not resulted in clinically useful drugs. Therefore, modulating Ras activity for targeted treatment of cancer remains an urgent healthcare need. In the current study, we investigated a novel class of compounds, the polyisoprenylated cysteinyl amide inhibitors (PCAIs), for their anticancer molecular mechanisms using the NSCLC cell panel with K-Ras and/or other mutant genes. Treatment of the lung cancer cells with PCAIs, NSL-RD-035, NSL-BA-036, NSL-BA-040, NSL-BA-055 and NSL-BA-040 resulted in concentration-dependent cell death in both K-Ras mutant (A549 and NCI-H1573), N-Ras mutant (NCI-H1299) and other (NCI-H661, NCI-H460, NCI-H1975, NCI-H1563) NSCLC cells. The PCAIs at sub- to low micromolar 1.0 -10 μM concentrations induced the degeneration of 3D spheroid cultures, inhibited, clonogenic cell growth, and induced marked apoptosis and cell cycle arrest, together with a significant increase in active caspase 3 (p<0.001). NSL-BA-040 at 5 μM prominently dislodged YFP-tagged K-Ras, but not H-Ras and N-Ras from the plasma membranes of transfected A549 and NCI-H661 cells. NSL-RD-035 attenuated the tumor growth of A549 cells in xenografted athymic mice in vivo. Taken together, PCAIs likely suppress NSCLC cell growth by disrupting growth signaling through the dislodgement of K-Ras the plasma membrane. Citation Format: FELIX AMISSAH, ELIZABETH NTANTIE, ROSEMARY A. POKU, AUGUSTINE T. NKEMBO, OLUFISAYO O. SALAKO, HERNAN FLORES-ROZAS, NAZARIUS S. LAMANGO. Dislodgement of K-Ras from plasma membranes, induction of apoptosis and tumor regression by PCAIs, a novel class of polyisoprenylated small molecules. [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 1869.