Triple-negative breast cancer (TNBC), a deadly and aggressive type of breast cancer, accounts for ~20% of human breast tumors. TNBC is often resistant to chemotherapy and radiotherapy and frequently recurs as distant metastases. The incidence of metastasis is higher in TNBC (~35%) than in other breast cancer types, and once TNBC metastasizes, it is considered incurable. Maternal embryonic leucine zipper kinase (MELK) is a redox and cell-cycle regulated kinase and a member of the adenosine monophosphate kinase-related kinase (AMPK-RK) family, which mediates cell survival under conditions of cellular stress. MELK has been shown to be a mediator of resistance to radiotherapy in breast cancer, as well as colorectal cancer and glioma stem cells. It is also associated with resistance to the chemotherapeutic agent, 5-FU, in colorectal cancer cells. The expression of MELK is significantly higher in TNBC than in other breast cancer types, and patients with MELK-overexpressing tumors have a higher mortality rate than patients with lower levels of MELK expression. However, how MELK promotes resistance to radiation and chemotherapy, and whether it mediates resistance to other DNA-damaging agents is unknown. Therefore, to evaluate its role in resistance to DNA damage-based radiotherapy and chemotherapy, we initiated a study to investigate whether MELK confers resistance to chemotherapeutic DNA-damaging agents that induce covalent DNA interstrand crosslinks (ICLs).  Our data suggest an entirely new function for MELK involving its translocation to the nucleus to interact with chromatin in response to DNA damage, where in a kinase-dependent manner, it facilitates error-prone repair of the DNA damage.

Investigation of the function of maternal embryonic leucine zipper kinase (MELK) in response to chemotherapeutic DNA-damaging agents in triple negative breast cancer

2019 Spring National Meeting

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