Cancer Chemotherapy and Pharmacology

, Volume 63, Issue 5, pp 807–818 | Cite as

Characterization of kinase suppressor of Ras-1 expression and anticancer drug sensitivity in human cancer cell lines

  • Scott M. Stoeger
  • Kenneth H. CowanEmail author
Original Article


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.


KSR1 NCI anticancer drug screen Drug resistance DNA damage Signal transduction 



We would like to thank Dr. Nick Scudiero for the frozen samples of each cell line and the select cell lines described in "Materials and methods", Dr. Robert Schultz for the compounds, and Dr. Susan Holbeck for help with the COMPARE analysis. We would also like to thank the laboratory of Dr. Robert Lewis for supplying the KSR1−/−, KSR1+/+, and the KSR1/GFP MEFs, as well as assistance in the use of the Li-Cor Odyssey system. SMS was supported by a Program of Excellence fellowship from the University of Nebraska Medical Center.


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Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  1. 1.Eppley Institute for Research in Cancer and Allied Diseases, 986805 Nebraska Medical CenterUniversity of Nebraska Medical CenterOmahaUSA

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