Abstract B19: The oncogenic TBX2 activates the ATM-CHK2-p53 axis to confer cisplatin resistance in breast cancer and melanoma

A prominent mechanism through which tumors develop resistance to DNA damaging chemotherapeutic agents is by cancer cells preferentially arresting in S-phase, thereby acquiring the ability to repair drug-induced DNA damage and consequently evading apoptosis. Combining DNA damaging therapies with targeted approaches that disrupt the DNA damage repair process may therefore prove to be more effective against such tumors. The developmentally important transcription factor TBX2 has been suggested as a novel anti-cancer drug target, as it is overexpressed in several cancers and possesses strong anti-senescence and pro-proliferative functions. Indeed, when TBX2 is silenced, we are able to reverse several features of transformation in both breast cancer and melanoma cells. We and others have previously showed that ectopic expression of TBX2 confers resistance to DNA damaging chemotherapeutic drugs, cisplatin and doxorubicin. However, whether endogenous TBX2 confers resistance to these DNA damaging agents in TBX2-driven cancers and the mechanism(s) by which this may occur have not been reported. To address this, we have silenced TBX2 in cisplatin-resistant breast cancer and melanoma cells and we show that knocking down TBX2 sensitizes the cells to cisplatin by disrupting the ATM-CHK2-p53 signalling cascade. Cell cycle analyses demonstrate that when TBX2 is knocked down there is an abrogation of an S-phase arrest but a robust G2/M arrest that correlates with a reduction in p-CHK2 and p53 levels. This prevents DNA repair resulting in TBX2 deficient cells entering mitosis with damaged DNA and consequently undergoing mitotic catastrophe. These results provide compelling evidence that targeting TBX2 in combination with chemotherapeutic drugs such as cisplatin could improve their efficacy and that it may be a viable treatment of TBX2-driven cancers. Citation Format: Serah Kimani, Sabina Wansbelen, Emily Davis, Jade Peres, Sharon Prince. The oncogenic TBX2 activates the ATM-CHK2-p53 axis to confer cisplatin resistance in breast cancer and melanoma. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Cancer Cell Cycle - Tumor Progression and Therapeutic Response; Feb 28-Mar 2, 2016; Orlando, FL. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(11_Suppl):Abstract nr B19.