While most forms of breast cancer (BC) are responsive towards chemotherapy, there is still a large unmet need for the treatment of resistant BCs, such as triple negative breast cancer (TNBC), which has undetectable estrogen receptor (ER), progesterone receptor (PR) as well as low amplification of human epidermal growth factor receptor 2 (HER2) levels. TNBC patients have low overall survival due to tumor recurrence, which is often accompanied by drug resistance.
We have recently developed a novel therapeutic approach targeting cellular adaptive survival mechanisms, which enable tumor cells to survive and proliferate in acidic, as well as nutrient and oxygen-deprived milieu. Although normal cells cannot proliferate under such conditions, cancer cells are able to thrive through these cellular adaptive survival mechanisms, such as autophagy, sustained unfolded protein response (UPR) or persistent endoplasmic reticulum stress (ERS). Our approach for treating resistant cancers is based on disrupting the ERS microenvironment using a small molecule that is able to modestly increase ERS and thus selectively trigger cancer cell apoptosis, without affecting normal cells. By systematically evaluating a prototype compound, we established the desired profile and potential uses for these therapeutics, which we termed ER stress aggravating agents (ERSA).