c-Myc high level amplification is associated with sensitivity to a CENP-E small molecular inhibitor, GSK923295A.

AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA 3612 Centromere-associated protein E (CENP-E) is expressed during mitosis and is essential for mitotic chromosomal alignments and the mitotic spindle check point. GSK923295A is a small molecule inhibitor of CENP-E. To facilitate the clinical development of GSK923295A we have screened more than 300 human cancer cell lines to search for genetic and genomic signatures that associate with response. The cell lines include representatives from cancer of the breast, lung, colon, ovary, prostate and other malignancies. We have generated genome wide copy number data from these lines, DNA sequence data from commonly mutated cancer genes and other genes of interest, and baseline mRNA and microRNA profiles. In a three-day proliferation assay the IC50 values for GSK923295A ranged from 10 nM to 10000 nM. Eighty-six percent of the cell lines had IC50 values of less than 100 nM and 14% of the lines were overtly resistant with IC50 values of >1000 nM. From this analysis, the most frequently sensitive cell lines were derived from lymphomas, myelomas, gliomas, sarcomas, melanomas, and ovarian cancers. The analysis of the first set of 30 lung cancer cell line data revealed amplification of the c-MYC gene in a third of the lines that were more sensitive to GSK923295A, and in none of the lines that were resistant to GSK923295A. This finding was confirmed by analyzing a second set of 24 lung cancer cell lines. We are now exploring the biological association of c-MYC and CENP-E inhibitor sensitivity to validate this potential predictive biomarker.