Get rid of pancreatic cancer by inhibiting garbage disposal?: Comment on "UAE1 Inhibition mediates the unfolded protein response, DNA damage and caspase-dependent cell death in pancreatic cancer" by Rehemtulla et al

Abstract

1. •

   stress pathways including the ER stress, the proteasome and the unfolded protein response (UPR) are increasingly reported to be suitable targets in PDAC

2. •

   UAE1 is the most abundant of two ubiquitin activating enzymes (UAE) regulating the initial step of the ER stress associated protein degradation (ERAD) pathway

3. •

   The group of Rehemtulla elegantly showed that TAK-243, a small molecule inhibitor of Ubiquitin activating enzyme 1 (UAE1) nduced apoptosis in PDAC cells and a subcutaneous mouse model of the disease

4. •

   In other preclinical models of cancer, especially in lymphatic malignancies, this compound showed promising results in directly inducing apoptosis but also in increasing the response to other conventional cytotoxic therapeutic approaches

5. •

   Strikingly, these effects were also reported in cells resistant to drugs that target other protein degradation pathways, like proteasome inhibitors, indicating divergent molecular mechanisms.

Keywords: ER stress; Pancreatic cancer; UAE1 inhibitor.