Inhibition of endoplasmic-reticulum-stress-mediated autophagy enhances the effectiveness of chemotherapeutics on pancreatic cancer

Abstract

The role of ER stress in pancreatic cancer pathobiology and inflammation has been increasingly recognized as an important factor in tumorigenesis and chemoresistance [15]. [...]certain anti-cancer therapeutics may chronically activate ER stress and autophagy, and such a drug-induced ER stress leads to the pro-survival response of the cancer cells, which consequently allows tumors to develop non-responsiveness to a particular chemotherapeutic [16, 17]. [...]understanding alternative molecular mechanisms that contribute to growth and survival of pancreatic adenocarcinoma would facilitate targeting of these pathways with potential for positive effects on treatment and prognosis. In further experiments, synergism was found by combining STF-083010 with FDA approved agents such as gemcitabine, oxaliplatin and bortezomib (Fig. 2d and data not shown). [...]selective inhibition of ER stress by IRE1α inhibitors could curb cancer cell growth and may increase the efficacy of several anti-tumor chemotherapeutics. [...]in our murine model, PDAC tissue exhibited significantly increased apoptosis and reduction in ductal cell growth upon treatment with sunitinib in combination with gemcitabine or chloroquine (Figs. 7 and 8).