A role for NRF-2 in the mechanism of action and effectiveness of dual tyrosine kinase inhibitor, lapatinib, in breast cancer cells


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Poornima Paramasivan1,Simon Langdon2,Yusuf Deeni1
1University of Abertay Dundee,2University of Edinburgh

Abstract

Background

Breast cancer is the most common cancer affecting over 1.5 million women each year and leading to greater number of cancer related deaths. HER receptor tyrosine kinases are frequently overexpressed in breast cancers. Despite the development of novel HER targeting receptor tyrosine kinase inhibitors (RTKIs) such as lapatinib, which targets both epidermal growth factor receptors (HER1 and HER2), development of drug resistance remains to be a major concern in breast cancer treatment. Nuclear factor erythroid 2-related factor (NRF2) is an important transcription factor in antioxidant response (AR) and oxidative stress regulation. NRF2 is cytoprotective and aberrantly activated in several breast cancer cells. Here we report a role of NRF2 in the mechanism of action and effectiveness of lapatinib in breast cancer cells.

Method

A panel of breast cancer cells, oestrogen receptor positive MCF-7 cells, HER2 overexpressing MCF-7/HER2 and SK-BR-3 cells, and luciferase ARE reporter MCF7-AREc32 cell lines were employed for the study. Cell viability, reactive oxygen species (ROS) levels, luciferase activity, NRF2, HO-1 and p-Akt protein levels were determined following treatment alone with lapatinib, bexarotene and ML385 or combination.

Results

Lapatinib inhibited the growth of breast cancer cell with persistent ROS generation, inhibition of NRF2, and reduced HO-1 and p-Akt levels. Using the ARE-driven luciferase reporter system of MCF7-AREc32 cell line, lapatinib treatment inhibited the NRF2/ARE-dependent transcriptional luciferase activity. Pharmacological inhibition of NRF2 by retinoid/rexinoid bexarotene or small molecule ML385 significantly increased the cytotoxic effect of lapatinib by disruption of AR pathway and significant accumulation of ROS in breast cancer cells, under HER receptor stimulated or unstimulated states.

Conclusion

Combining lapatinib with NRF2 inhibitor bexarotene or ML385 showed greater anticancer efficacy than lapatinib alone, suggesting that the effectiveness of HER targeting RTKIs like lapatinib in breast cancer could be enhanced by parallel inhibition of the NRF2-dependent AR pathway.