NQO1-dependent, tumor-selective radiosensitization of non-small cell lung cancers

Abstract

Purpose:

Development of tumor-specific therapies for the treatment of recalcitrant non-small cell lung cancers (NSCLCs) are urgently needed. Here, we investigated the ability of ß-lapachone (ß-lap, ARQ761 in clinical form) to selectively potentiate the effects of ionizing radiation (IR, 1–3 Gy) in NSCLCs that over-express NAD(P)H:Quinone Oxidoreductase 1 (NQO1). Experimental Design:

The mechanism of lethality of low dose IR in combination with sublethal doses of ß-lap were evaluated in NSCLC lines in vitro and validated in subcutaneous and orthotopic xenograph models in vivo. Pharmacokinetics and pharmacodynamics (PK/PD) studies comparing single versus co-treatments were performed to validate therapeutic efficacy and mechanism of action. Results:

ß-Lap administration after IR treatment hyperactivated PARP, greatly lowered NAD+/ATP levels, and increased DSB lesions over time in vitro. Radiosensitization of orthotopic, as well as subcutaneous, NSCLCs occurred with high apparent cures (>70%), even though 1/8 ß-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 + ß-lap treatments hyperactivate PARP activity, greatly lower NAD+/ATP levels and dramatically inhibit DSB repair in exposed NQO1+ cancer tissue, while low NQO1 levels and high levels of Catalase in associated normal tissue were protective. Conclusion:

Our data suggest that combination of sublethal doses of ß-lap and IR is a viable approach to selectively treat NQO1-overexpressing NSCLC and warrant a clinical trial using low-dose IR + ß-lapachone against patients with NQO1+ NSCLCs.