Targeting the inositol requiring enzyme 1 alpha (IRE1) stress response pathway may improve responses to chemotherapy and reduce relapses for patients with triple negative breast cancer (TNBC), researchers have shown for the first time.
There are no targeted therapies available for TNBC and chemotherapy is the mainstay treatment, with a high relapse rate and poor long-term prognosis.
The study, published in Nature Communications, found that IRE1, a cellular stress sensor that normally acts to alleviate short-term stresses within cells, such as lack of nutrients or oxygen, is a central driver of treatment-related relapse in TNBC.
Using TNBC cells treated with chemotherapy (paclitaxel), the researchers found that blocking IRE1 activity using a small molecule inhibitor (MKC8866) reduced the production of survival signals, and thus the growth of new cancer cells by 50 per cent.
In a pre-clinical (mouse) model of TNBC, MKC8866 increased the effectiveness of paclitaxel, leading to regression of eight out of 10 cancers compared to regression of three out of 10 cancers using paclitaxel alone, and also reduced tumour relapse.
An analysis of 595 breast cancer patient tumours showed that TNBC tumours displayed the highest IRE1 activity compared to other subtypes, suggesting that IRE1 may be of particular importance in TNBC.