NQO1-dependent, Tumor-selective Radiosensitization of Non-small Cell Lung Cancers.

Abstract

Development of tumor-specific therapies for the treatment of recalcitrant non-small cell lung cancers (NSCLC) is urgently needed. Here, we investigated the ability of β-lapachone (β-lap, ARQ761 in clinical form) to selectively potentiate the effects of ionizing radiation (IR, 1-3 Gy) in NSCLCs that overexpress NAD(P)H:Quinone Oxidoreductase 1 (NQO1). The mechanism of lethality of low-dose IR in combination with sublethal doses of β-lap was evaluated in NSCLC lines <i>in vitro</i> and validated in subcutaneous and orthotopic xenograft models <i>in vivo</i>. Pharmacokinetics and pharmacodynamics (PK/PD) studies comparing single versus cotreatments were performed to validate therapeutic efficacy and mechanism of action. β-Lap administration after IR treatment hyperactivated PARP, greatly lowered NAD⁺/ATP levels, and increased double-strand break (DSB) lesions over time <i>in vitro</i>. Radiosensitization of orthotopic, as well as subcutaneous, NSCLCs occurred with high apparent cures (>70%), even though 1/8 β-lap doses reach subcutaneous versus orthotopic tumors. No methemoglobinemia or long-term toxicities were noted in any normal tissues, including mouse liver that expresses the highest level of NQO1 (∼12 units) of any normal tissue. PK/PD responses confirm that IR + β-lap treatments hyperactivate PARP activity, greatly lower NAD⁺/ATP levels, and dramatically inhibit DSB repair in exposed NQO1⁺ cancer tissue, whereas low NQO1 levels and high levels of catalase in associated normal tissue were protective. Our data suggest that combination of sublethal doses of β-lap and IR is a viable approach to selectively treat NQO1-overexpressing NSCLC and warrant a clinical trial using low-dose IR + β-lap against patients with NQO1⁺ NSCLCs.