Eliminating hypoxic tumor cells improves response to PARP inhibitors in homologous recombination–deficient cancer models
Manal Mehibel, … , Erinn B. Rankin, Amato J. Giaccia
Manal Mehibel, … , Erinn B. Rankin, Amato J. Giaccia
Published June 1, 2021
Citation Information: J Clin Invest. 2021;131(11):e146256. https://doi.org/10.1172/JCI146256.
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Research Article Cell biology Oncology

Eliminating hypoxic tumor cells improves response to PARP inhibitors in homologous recombination–deficient cancer models

Abstract

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.

Authors

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

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Figure 8

HR-deficient xenografts are sensitive to TPZ and PARPi combination treatment.

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HR-deficient xenografts are sensitive to TPZ and PARPi combination treat...
(A) Schematic diagram of models for treatment of HR-deficient cells in vivo. Mice were injected subcutaneously with tumor cells. After tumors reached an approximate size of 100 mm3, mice were divided into vehicle and treatment groups. (B) OVCAR8 xenograft model. Left panel: growth curves of OVCAR8 tumors in control mice and mice treated with 50 mg/kg olaparib and/or 20mg/kg TPZ. Two-way ANOVA: vehicle versus combination interaction, P < 0.0001; olaparib versus combination interaction, P < 0.0001; TPZ versus combination interaction, P < 0.0001; n = 5 mice in each group. Right panel: relative enzymatic PARP activity of tumor lysates collected 2 hours after the final olaparib treatment. Each dot represents data from 1 tumor. *P < 0.05, t test. See also Supplemental Figure 6A. (C) SUM149 xenograft model. Left panel: growth curves of SUM149 tumors in control mice and mice treated with 0.1 mg/kg talazoparib and/or 20 mg/kg TPZ. Vehicle versus combination: 2-way ANOVA, interaction, P < 0.0001; talazoparib versus combination: 2-way ANOVA, interaction, P < 0.0001; TPZ versus combination: 2-way ANOVA, interaction, P < 0.0001. n = 5 mice in each group. Right panel; relative enzymatic PARP activity of tumor lysates collected 2 hours after final talazoparib treatment. Each dot represents data from 1 tumor. P < 0.05, by t test. See also Supplemental Figure 6, B and C. Data are represented as mean SEM (represented by error bars).