Division of Radiation and Cancer Biology, Department of Radiation Oncology, Stanford University Medical Center, Stanford, California, USA.
Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, California, USA.
J Clin Invest. 2021 Jun 1;131(11). doi: 10.1172/JCI146256.
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. To determine the contribution of hypoxia to PARPi resistance in tumors, we used the hypoxic cytotoxin tirapazamine to selectively kill hypoxic tumor cells. We found that the selective elimination of hypoxic tumor cells led to a substantial antitumor response when used with PARPi compared with that in tumors treated with PARPi alone, without enhancing normal tissue toxicity. Since human breast cancers with BRAC1/2 mutations have an increased hypoxia signature and hypoxia reduces the efficacy of PARPi, then eliminating hypoxic tumor cells should enhance the efficacy of PARPi therapy.
缺氧是肿瘤微环境的一个标志性特征，会导致对常规化疗产生耐药性，但最近有报道称，在同源重组功能正常（HR 功能正常）的细胞中，缺氧与聚（ADP-核糖）聚合酶抑制剂（PARPi）协同作用，通过抑制 HR 来实现协同杀伤。虽然这种协同杀伤作用发生在严重缺氧（<0.5%氧气）下，但我们的研究表明，中度缺氧（2%氧气）反而会在 HR 功能正常和缺陷的癌细胞中促进 PARPi 耐药性。从机制上讲，我们发现 ROS 诱导的 DNA 损伤减少是导致观察到的耐药性的原因。为了确定缺氧对肿瘤中 PARPi 耐药性的贡献，我们使用缺氧细胞毒素替拉扎胺选择性地杀死缺氧肿瘤细胞。我们发现，与单独使用 PARPi 治疗的肿瘤相比，与 PARPi 联合使用时，选择性消除缺氧肿瘤细胞会导致显著的抗肿瘤反应，而不会增强正常组织毒性。由于具有 BRAC1/2 突变的人类乳腺癌具有增加的缺氧特征，并且缺氧会降低 PARPi 的疗效，因此消除缺氧肿瘤细胞应该会增强 PARPi 治疗的疗效。
