ANTICANCER AND CHEMOSENSITIZING EFFECTS OF WEE‐1 KINASE INHIBITOR MK‐1775 IN TRIPLE NEGATIVE (MB‐231) BREAST CANCER CELLS

Abstract

Current breast cancer classification included cells that express estrogen (ER) and progesterone (PR) receptors, those with ERBB2 (HER‐2/Neu) amplification, and those without expression of ER, PR, or amplification of ERBB2 (referred to as triple‐negative or basal‐like breast cancer). Triple negative breast cancers are generally more difficult to treat, are known to be more aggressive and with poor prognosis. Several molecular mechanisms have been identified as potential targets for development of drugs to treat breast cancer including cell cycle checkpoints kinases. The G2/M cell‐cycle protein tyrosine kinase, Wee‐1, plays a crucial role in the checkpoint arrest for DNA repair before mitotic entry. Under normal conditions, cells repair damaged DNA during G1 arrest; however, cancer cells often have a deficient G1/S (p53) checkpoint and depend on a functional G2/M checkpoint for DNA repair. MK‐1775 is a well‐characterized Wee‐1 kinase inhibitor with significant evidence supporting its potential use as anti‐cancer and/or chemosensitizing drug. Working hypothesis proposed for this project was that use of Wee‐1 kinase inhibitors in triple negative breast cancer cells can result in profound and significant anticancer and chemosensitizing effects. In order to test this hypothesis we performed a series of dose response experiments using DNA‐Damaging agents or treatments (DNA‐dt: Ex. Cisplatin, 5‐Fluororacil and Doxorubicin) alone and/or in combination with MK‐1775. Cytotoxic effects of these treatments where evaluated with the MDA‐MB‐231 triple negative breast cancer cells as our model system and the 384‐well plate/96 hours/resazurin (AlamarBlue) cell proliferation assay. Analysis of these results included determination of half maximal inhibitory or effective concentration (IC50 or EC50) for each drug treatment and/or combinations followed by assessment of synergy and/or antagonism analysis based on Combenefit software package. Use of this software allows for visualization, analysis and quantification of drug combination effects including surface analyses of drug combinations to identify synergy using classical synergy models. Initial preliminary results indicated IC50/EC50 values for cisplatin (5.88μM), 5‐Fluorouracil (82.55μM), Doxorubicin (0.353μM), and MK‐1775 (0.307μM) similar to the ones reported in the literature. Moreover, initial results are also consistent with a significant degree of potentiation or chemosensitization of MB‐231 cells to the cytotoxic effects of our selected DNA‐dt when combined with low MK‐1775 concentrations. Taken together, our preliminary results are consistent with a potential role of Wee‐1 kinase inhibitors like MK‐17175 as anticancer and/or chemosensitizing agents against triple‐negative or basal‐like breast cancer cells.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.