Abstract C130: The oncogenic transcription factors TBX2 and TBX3 as attractive targets for anticancer drug development

• Published in: Molecular cancer therapeutics 2015-12, Vol.14 (12_Supplement_2), p.C130-C130
• Main Authors: Kimani, Serah, Ballim, Deeya, Sewell, Trevor, Sturrock, Edward, Prince, Sharon
• Format: Article
• Language: English
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.TARG-15-C130

TBX2 and TBX3 are transcription factors that play critical roles in embryonic development but have no known function in adult tissue, and their overexpression has been associated with a growing list of cancers including melanoma, sarcomas, breast, pancreatic, liver and bladder cancers (1). Previous studies in our laboratory have shown that TBX2 and TBX3 play central but different roles in oncogenesis, where TBX2 functions as a potent growth promoting factor and TBX3 contributes to tumour formation, metastasis and invasion (2-4). Additionally, our data have demonstrated that TBX2 confers resistance to cisplatin by promoting DNA repair and may also promote oncogenesis through inappropriate survival of cells with damaged DNA (5). Recent work from our group has provided strong in vitro and in vivo biological evidence that TBX2 and TBX3 are novel targets for development of anti-cancer drugs for cancers where they are overexpressed. Knocking down TBX2 by shRNA induces senescence in advanced melanoma cells, and it results in profound inhibition of proliferation of several metastatic breast cancer cell lines (2,6). Furthermore, depleting TBX2 in metastatic melanoma and cisplatin-resistant breast cancer cells leads to their sensitization to this widely used chemotherapeutic drug, suggesting that targeting TBX2 in combination with currently used therapies could improve their efficacy (5). On the other hand, when TBX3 is depleted by shRNA in some breast cancers and melanomas, cells display reduced anchorage independence, cell migration, colony forming ability and a less aggressive phenotype (2). We are in the process of exploring ways of identifying potential inhibitors of TBX2/TBX3 oncogenic activity by combining a structure-based approach that focuses on molecular recognition and interaction of TBX2/TBX3 with their target genes, and a medium throughput approach involving screening of small molecule libraries. References [1] Wansleben S, Peres J, Hare S, Goding CR, Prince S (2014) BBA - Reviews on Cancer, 1846, 380-391. [2] Peres J, Davis E, Mowla S, Bennet DC, Li JA, Wansleben S and Prince S (2010) Genes & Cancer, 1(3):272-282. [3] Mowla S, Pinnock R, Leaner VD, Goding CR, Prince S (2010) The Biochemical journal, 433(1): 145-53. [4] Peres J, Prince S (2013) Molecular cancer, 12:117.DOI: 10.1186/1476-4598-12-117. [5] Wansleben S, Davis E, Peres J, Prince S (2013) Cell Death and Disease, 4, e846; doi:10.1038/cddis.2013.365. [6] Redmond, K.L., Crawford, N.T., Farmer,