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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 (NSCLC) is urgently needed. Here, we investigated the ability of ?-lapachone (?-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 low-dose IR in combination with sublethal doses of ?-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:?-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 ?-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 + ?-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 ?-lap and IR is a viable approach to selectively treat NQO1-overexpressing NSCLC and warrant a clinical trial using low-dose IR + ?-lap against patients with NQO1+ NSCLCs.

SUBMITTER: Motea EA

PROVIDER: S-EPMC6788754 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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

Motea Edward A EA Huang Xiumei X Singh Naveen N Kilgore Jessica A JA Williams Noelle S NS Xie Xian-Jin XJ Gerber David E DE Beg Muhammad S MS Bey Erik A EA Boothman David A DA

Clinical cancer research : an official journal of the American Association for Cancer Research 20190107 8

<h4>Purpose</h4>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).<h4>Experimental design</h4>The mechanism of lethality of low-dose IR in combination with sublethal doses of β-lap was evaluated in ...[more]

PMID: 30617135

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Project description:BackgroundNon-small cell lung cancer (NSCLC), a leading cause of cancer deaths, represents a heterogeneous group of neoplasms, mostly comprising squamous cell carcinoma (SCC), adenocarcinoma (AC) and large-cell carcinoma (LCC). The objectives of this study were to utilize integrated genomic data including copy-number alteration, mRNA, microRNA expression and candidate-gene full sequencing data to characterize the molecular distinctions between AC and SCC.MethodsComparative genomic hybridization followed by mutational analysis, gene expression and miRNA microarray profiling were performed on 123 paired tumor and non-tumor tissue samples from patients with NSCLC.ResultsAt DNA, mRNA and miRNA levels we could identify molecular markers that discriminated significantly between the various histopathological entities of NSCLC. We identified 34 genomic clusters using aCGH data; several genes exhibited a different profile of aberrations between AC and SCC, including PIK3CA, SOX2, THPO, TP63, PDGFB genes. Gene expression profiling analysis identified SPP1, CTHRC1 and GREM1 as potential biomarkers for early diagnosis of the cancer, and SPINK1 and BMP7 to distinguish between AC and SCC in small biopsies or in blood samples. Using integrated genomics approach we found in recurrently altered regions a list of three potential driver genes, MRPS22, NDRG1 and RNF7, which were consistently over-expressed in amplified regions, had wide-spread correlation with an average of ~800 genes throughout the genome and highly associated with histological types. Using a network enrichment analysis, the targets of these potential drivers were seen to be involved in DNA replication, cell cycle, mismatch repair, p53 signalling pathway and other lung cancer related signalling pathways, and many immunological pathways. Furthermore, we also identified one potential driver miRNA hsa-miR-944.ConclusionsIntegrated molecular characterization of AC and SCC helped identify clinically relevant markers and potential drivers, which are recurrent and stable changes at DNA level that have functional implications at RNA level and have strong association with histological subtypes.

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

Publications

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

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