Reference profiling of the genomic response induced by an antimicrotubule agent, TZT-1027 (Soblidotin), in vitro

TZT-1027 is an antimicrotubule agent targeting beta-tubulin that is undergoing clinical development. The genomic response of cancer cells to TZT-1027 was profiled to evaluate its biochemical activity. A lung cancer cell line, PC-14, was exposed to antimicrotubule agents including dolastatins, Vinca alkaloids and taxanes at an equivalent toxicity level. Alterations in the TZT-1027-induced gene expression of approximately 600 genes were then examined using microarray technology and the resulting gene profiles were compared with those for cells exposed to the other antimicrotubule agents. A principle component analysis using the whole gene set demonstrated that TZT-1027 produced similar gene profiles to those produced by dolastatin 10, but that these gene profiles differed from those produced by other agents. The agents were classified according to their induced genomic response in a molecular structure-dependent manner. Genes whose expression profiles differed according to drug class included intermediate filaments, extracellular matrix protein and Rho regulatory genes that may be involved in cytoskeletal and angiogenesis processes that are regulated by microtubule dynamics. TZT-1027 produces a unique genomic response profile distinct from that of Vinca alkaloids and taxanes, suggesting that this agent has a different mechanism of action. The selected genes may act as pharmacodynamic biomarkers allowing the unique mode of action of TZT-1027 to be discriminated from those of other antimicrotubule agents.