Manal Mehibel, Yu Xu, Caiyun G Li, Eui Jung Moon, Kaushik N Thakkar, Anh N Diep, Ryan K Kim, Joshua D Bloomstein, Yiren Xiao, Julien Bacal, Joshua C Saldivar, Quynh-Thu Le, Karlene A Cimprich, Erinn B Rankin, Amato J Giaccia
Hypoxia, a hallmark feature of the tumor microenvironment, causes resistance to conventional chemotherapy, but was recently reported to synergize with poly(ADP-ribose) polymerase inhibitors (PARPis) in homologous recombination-proficient (HR-proficient) cells through suppression of HR. While this synergistic killing occurs under severe hypoxia (<0.5% oxygen), our study shows that moderate hypoxia (2% oxygen) instead promotes PARPi resistance in both HR-proficient and -deficient cancer cells. Mechanistically, we identify reduced ROS-induced DNA damage as the cause for the observed resistance...
June 1, 2021: Journal of Clinical Investigation