Pharmacological arginine deprivation renders pancreatic cancer cells susceptible to senolysis and inhibition of the integrated stress response

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is almost inevitably fatal and largely resistant to current chemotherapy regimens. Senolysis, i. e. the selective elimination of senescent cells, and the targeting of cancer specific cellular metabolism are two novel treatment approaches that have proven to be effective for a variety of cancer types in pre-clinical studies. We now demonstrate that pharmacological depletion of arginine with pegylated recombinant human arginase 1 (PEG-rhARG1) induced senescence and activated the integrated stress response (IRS) in PDAC cells. Cells treated in such a manner were strikingly susceptible towards senolysis with ABT-263 (navitoclax) and also sensitive towards inhibition of the IRS. These results demonstrate a novel mechanism for an induced sensitivity of PDAC cells that could be exploited for cancer therapy.