Abstract 4125: Identification of candidate predictive biomarkers for the cdc7 kinase inhibitor BMS-863233/XL413
Authors: Geese William J. , Xing Guan , Hu Beihong , DeSilva Heshani , Oppenheimer Simone , Fairchild Craig , Rowley Bruce , Ross-MacDonald Petra , Fargnoli Joseph , Woolfson Adrian , Huang Fei 
Published: August 2014

Cdc7 is a serine-threonine kinase that plays a critical role in the licensing of DNA replication origins and has been shown to play a role in DNA damage-induced checkpoint responses. Inhibition of cdc7 activity can block DNA replication, arrest cell cycle progression and can also result in apoptosis. Because of its proximal role in DNA replication, cdc7 kinase represents a novel therapeutic target for cancer treatment that has the potential to provide better control and fewer side effects than traditional chemotherapeutic agents that function distally during chain elongation. To complement the clinical development of BMS-863233/XL413, an ATP-competitive reversible cdc7 kinase inhibitor, we used cell line models to identify gene expression markers that are potentially predictive of a clinical response to BMS-863233/XL413. The in vitro sensitivity for BMS-863233/XL413 was established in a panel of 64 cell lines of mixed histotypes. Neither mutational status (as defined by the Sanger Institute COSMIC database), doubling time nor cdc7, ask/dbf4 or mcm2 basal mRNA expression were significantly associated with intrinsic sensitivity. Using gene expression profiling, we identified an intrinsic sensitivity gene signature consisting of 63 candidate genes whose basal expression was significantly associated with intrinsic sensitivity to BMS-863233/XL413. Evaluation of these markers using the Oncomine™ platform demonstrated enrichment in the ER/PR/HER2-negative breast cancer subtype. Dose titration studies revealed that 49 of these candidate genes were responsive to BMS-863233/XL413 treatment; 17 had IC50 values &lt; 50 uM. A cell line model of acquired resistance to BMS-863233/XL413 was developed and was found to display an overlapping gene expression signature similar to the intrinsic sensitivity signature. Pathway analysis of differentially expressed genes in the acquired resistance model showed enrichment for genes involved in cell cycle and checkpoint functions. Among nine genes associated with intrinsic sensitivity, responsive to BMS-863233/XL413 treatment and that were differentially expressed in the acquired resistance model, seven (RBMS1, CD55, UGCG, NOL3, DUSP5, FOSL2 and PLK2) are biologically plausible, playing roles in cell cycle regulation, cellular proliferation and/or apoptosis. In conclusion, we identified candidate gene expression markers which are potentially predictive of a clinical response to the cdc7 inhibitor BMS-863233/XL413. These markers appear to be enriched in triple negative breast cancer–a patient population with poor prognosis and few effective treatment options–suggesting the potential for clinical efficacy following cdc7 inhibition in this population. Some of these markers are likely to play a role in the biology of intrinsic and acquired resistance to cdc7 inhibition and may consequently serve as potential surrogate pharmacodynamic endpoints.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4125. doi:10.1158/1538-7445.AM2011-4125