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

• Published in: Clinical cancer research 2019-04, Vol.25 (8), p.2601-2609
• Main Authors: Motea, Edward A, Huang, Xiumei, Singh, Naveen, Kilgore, Jessica A, Williams, Noelle S, Xie, Xian-Jin, Gerber, David E, Beg, Muhammad S, Bey, Erik A, Boothman, David A
• Format: Article
• Language: English
• Subjects: Animals; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - metabolism; Carcinoma, Non-Small-Cell Lung - radiotherapy; Cell Line, Tumor; Disease Models, Animal; Dose-Response Relationship, Radiation; Humans; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Lung Neoplasms - radiotherapy; Mice; NAD(P)H Dehydrogenase (Quinone) - genetics; Naphthoquinones - pharmacology; Poly(ADP-ribose) Polymerases - metabolism; Radiation Tolerance - genetics; Radiation, Ionizing; Radiation-Sensitizing Agents - pharmacology; Treatment Outcome; Xenograft Model Antitumor Assays
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-18-2560

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 and validated in subcutaneous and orthotopic xenograft models . 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 . 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.