Genomic Deregulation And Therapeutic Role Of The Cell-Cycle Kinase Tlk2 In More Aggressive Breast Cancers

More aggressive breast cancers often coincide with enhanced chromosomal instability (CIN), which poses a great challenge to clinical management. By integrative analysis of genomic data, we observed the amplification of tousled-like kinase 2 (TLK2), a cell cycle serine-threonine kinase, in approximately 9% of breast cancer, which is more frequent in the luminal B and late-stage breast tumors. The resulting TLK2 upregulation correlates with the level of CIN in breast tumors, and predicts worse outcome regardless of endocrine therapy. Further studies suggest that TLK2 overexpression leads to a G2/M checkpoint defect, delayed DNA repair, and enhanced invasiveness. TLK2 silencing selectively inhibits the growth of TLK2-high breast cancer cells, and induces apoptosis. This response is retained in the breast cancer cells with acquired endocrine resistance. TLK2 inhibition in a preclinical tumor model significantly improved progression-free survival. Together, targeting TLK2 presents an attractive therapeutic strategy on TLK2-amplified breast cancers. Citation Format: Jin-Ah KIM, Ying Tan, Xian Wang, Xixi Cao, Jamunarani Veeraraghavan, Yulong Liang, Dean P. Edwards, Xuewen Pan, Kaiyi Li, Rachel Schiff, Xiaosong Wang. Genomic deregulation and therapeutic role of the cell-cycle kinase TLK2 in more aggressive breast cancers. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3032. doi:10.1158/1538-7445.AM2015-3032