CBP501 is an anticancer
drug candidate that was investigated in two randomized phase II clinical trials for patients with nonsquamous
non-small cell lung cancer (NSCLC) and
malignant pleural mesothelioma (MPM).
CBP501 has been shown to have two mechanisms of action, namely
calmodulin modulation and G2 checkpoint abrogation. Here, we searched for a
biomarker to predict sensitivity to
CBP501. Twenty-eight NSCLC cell lines were classified into two subgroups, CBP501-sensitive and -insensitive, by quantitatively analyzing the cis-diamminedichloro-
platinum (II) (CDDP)-enhancing activity of
CBP501 through treatments with short-term (1 hour) coexposure to CDDP and
CBP501 or to either alone. Microarray analysis was performed on these cell lines to identify gene expression patterns that correlated with
CBP501 sensitivity. We found that multiple nuclear factor erythroid-2-related factor 2 (Nrf2) target genes showed high expression in CBP501-insensitive cell lines. Western blot and immunocytochemical analysis for Nrf2 in NSCLC cell lines also indicated higher
protein level in CBP501-insensitive cell lines. Moreover,
CBP501 sensitivity is modulated by silencing or
sulforaphane-induced overexpression of Nrf2. These results indicate that Nrf2
transcription factor is a potential candidate as a
biomarker for resistance to
CBP501. This study might help to identify those subpopulations of patients who would respond well to the
CBP501 and CDDP combination treatment of NSCLC.