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

Edward A. Motea, Xiumei Huang, Naveen Singh, Jessica A. Kilgore, Noelle S Williams, Xian-Jin Xie, David E Gerber, Muhammad S Beg, Erik A. Bey, David A Boothman

Research output: Contribution to journalArticle

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Abstract

Purpose: 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). Experimental Design: The mechanism of lethality of lowdose IR in combination with sublethal doses of β-lap was evaluated in NSCLC lines in vitro and validated in subcutaneous and orthotopic xenograft models in vivo. Pharmacokinetics and pharmacodynamics (PK/PD) studies comparing single versus cotreatments were performed to validate therapeutic efficacy and mechanism of action. Results: β-Lap administration after IR treatment hyperactivated PARP, greatly lowered NAD+/ATP levels, and increased double-strand break (DSB) lesions over time in vitro. 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. Conclusions: 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.

Original languageEnglish (US)
Pages (from-to)2601-2609
Number of pages9
JournalClinical Cancer Research
Volume25
Issue number8
DOIs
StatePublished - Apr 15 2019

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Non-Small Cell Lung Carcinoma
NAD
Neoplasms
Pharmacokinetics
Adenosine Triphosphate
Methemoglobinemia
Therapeutics
Ionizing Radiation
Heterografts
Catalase
Oxidoreductases
Research Design
Clinical Trials
Liver
In Vitro Techniques

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Motea, E. A., Huang, X., Singh, N., Kilgore, J. A., Williams, N. S., Xie, X-J., ... Boothman, D. A. (2019). NQO1-dependent, tumor-selective radiosensitization of non-small cell lung cancers. Clinical Cancer Research, 25(8), 2601-2609. https://doi.org/10.1158/1078-0432.CCR-18-2560

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

In: Clinical Cancer Research, Vol. 25, No. 8, 15.04.2019, p. 2601-2609.

Research output: Contribution to journalArticle

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. / NQO1-dependent, tumor-selective radiosensitization of non-small cell lung cancers. In: Clinical Cancer Research. 2019 ; Vol. 25, No. 8. pp. 2601-2609.
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abstract = "Purpose: 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). Experimental Design: The mechanism of lethality of lowdose IR in combination with sublethal doses of β-lap was evaluated in NSCLC lines in vitro and validated in subcutaneous and orthotopic xenograft models in vivo. Pharmacokinetics and pharmacodynamics (PK/PD) studies comparing single versus cotreatments were performed to validate therapeutic efficacy and mechanism of action. Results: β-Lap administration after IR treatment hyperactivated PARP, greatly lowered NAD+/ATP levels, and increased double-strand break (DSB) lesions over time in vitro. 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. Conclusions: 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.",
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AU - Williams, Noelle S

AU - Xie, Xian-Jin

AU - Gerber, David E

AU - Beg, Muhammad S

AU - Bey, Erik A.

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