Previous studies have indicated that the ERK1/2 MAP kinase signaling pathway plays an important role not only in cell growth, cell cycle regulation, and differentiation, but also in determining the sensitivity of cells to
anticancer agents as well. Furthermore, expression of
kinase suppressor of Ras-1 (KSR1), a molecular scaffold that modulates signaling through the ERK1/2 MAP
kinase pathway, has been shown to influence the cellular sensitivity to the
anticancer agent cisplatin. To further define the role of KSR1 expression on
drug sensitivity, the expression of KSR1 was examined in the NCI60 anticancer
drug screen, a panel of
cancer cell lines representing nine tissue types, established by the Developmental
Therapeutics Program (DTP) at the National Cancer Institute (NCI). The expression of thousands of molecular targets has been examined in the NCI60 panel as well as the cellular toxicity for greater than 400,000 compounds. KSR1 expression varied almost 30-fold difference between the highest and lowest expressing cell lines in the NCI60. Using the COMPARE analysis algorithm, KSR1 expression was correlated with sensitivity of the compounds screened by DTP and several novel agents were identified whose sensitivity correlated with KSR1 expression in the NCI60 panel. Cytotoxicity of two agents,
cytochalasin H and
tunicamycin, identified through the COMPARE analysis of KSR1 expression and
drug sensitivity, was also examined in wild type (KSR(+/+)) mouse embryo fibroblasts (MEFs) and MEFs deficient in KSR1 expression (KSR1(-/-)). These studies demonstrated enhanced sensitivity, as well as increased ERK activation, in KSR(-/-) MEFs following exposure to
tunicamycin or
cytochalasin H compared to KSR(+/+) MEFs. Furthermore, restoration of KSR1 expression in KSR(-/-) MEFs following stable transduction of cells with a KSR1 expression vector, enhanced sensitivity of cells to
tunicamycin and
cytochalasin H and decreased ERK1/2 activation following exposure to these drugs. In addition, the sensitivity to
cytochalasin H and
tunicamycin of
breast cancer cell lines with low KSR1 expression, (HS578T and MDA-MB-231/ATCC), was increased relative to the sensitivity of
breast cancer cells with higher levels of KSR1 (MCF7). These studies indicate that KSR1 may play an important role in the determination of cellular sensitivity to
anticancer agents.