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Two novel determinants of etoposide resistance in small cell lung cancer.

ABSTRACT: Patient survival in small cell lung cancer (SCLC) is limited by acquired chemoresistance. Here we report the use of a biologically relevant model to identify novel candidate genes mediating in vivo acquired resistance to etoposide. Candidate genes derived from a cDNA microarray analysis were cloned and transiently overexpressed to evaluate their potential functional roles. We identified two promising genes in the DNA repair enzyme DNA polymerase ? and in the neuroendocrine transcription factor NKX2.2. Specific inhibition of DNA polymerase ? reduced the numbers of cells surviving treatment with etoposide and increased the amount of DNA damage in cells. Conversely, stable overexpression of NKX2.2 increased cell survival in response to etoposide in SCLC cell lines. Consistent with these findings, we found that an absence of nuclear staining for NKX2.2 in SCLC primary tumors was an independent predictor of improved outcomes in chemotherapy-treated patients. Taken together, our findings justify future prospective studies to confirm the roles of these molecules in mediating chemotherapy resistance in SCLC.

SUBMITTER: Lawson MH

PROVIDER: S-EPMC3145147 | biostudies-literature | 2011 Jul

REPOSITORIES: biostudies-literature

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Two novel determinants of etoposide resistance in small cell lung cancer.

Lawson Malcolm H MH Cummings Natalie M NM Rassl Doris M DM Russell Roslin R Brenton James D JD Rintoul Robert C RC Murphy Gillian G

Cancer research 20110603 14

Patient survival in small cell lung cancer (SCLC) is limited by acquired chemoresistance. Here we report the use of a biologically relevant model to identify novel candidate genes mediating in vivo acquired resistance to etoposide. Candidate genes derived from a cDNA microarray analysis were cloned and transiently overexpressed to evaluate their potential functional roles. We identified two promising genes in the DNA repair enzyme DNA polymerase β and in the neuroendocrine transcription factor N ...[more]

PMID: 21642373

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Project description:BACKGROUND:Metabolic reprogramming contributes significantly to tumor development and is tightly linked to drug resistance. The chemotherapeutic agent etoposide (VP-16) has been used clinically in the treatment of lung cancer but possess different sensitivity and efficacy towards SCLC and NSCLC. Here, we assessed the impact of etoposide on glycolytic metabolism in SCLC and NSCLC cell lines and investigated the role of metabolic rewiring in mediating etoposide resistance. METHODS:glycolytic differences of drug-treated cancer cells were determined by extracellular acidification rate (ECAR), glucose consumption, lactate production and western blot. DNA damage was evaluated by the comet assay and western blot. Chemoresistant cancer cells were analyzed by viability, apoptosis and western blot. Chromatin immunoprecipitation (ChIP) was used for analysis of DNA-protein interaction. RESULTS:Here we showed that exposure to chemotherapeutic drug etoposide induces an exacerbation of ROS production which activates HIF-1?-mediated the metabolic reprogramming toward increased glycolysis and lactate production in non-small cell lung cancer (NSCLC). We identified lactic acidosis as the key that confers multidrug resistance through upregulation of multidrug resistance-associated protein 1 (MRP1, encoded by ABCC1), a member of ATP-binding cassette (ABC) transporter family. Mechanistically, lactic acid coordinates TGF-?1/Snail and TAZ/AP-1 pathway to induce formation of Snail/TAZ/AP-1 complex at the MRP1/ABCC1 promoter. Induction of MRP1 expression inhibits genotoxic and apoptotic effects of chemotherapeutic drugs by increasing drug efflux. Furthermore, titration of lactic acid with NaHCO3 was sufficient to overcome resistance. CONCLUSIONS:The chemotherapeutic drug etoposide induces the shift toward aerobic glycolysis in the NSCLC rather than SCLC cell lines. The increased lactic acid in extracellular environment plays important role in etoposide resistance through upregulation of MRP expression. These data provide first evidence for the increased lactate production, upon drug treatment, contributes to adaptive resistance in NSCLC and reveal potential vulnerabilities of lactate metabolism and/or pathway suitable for therapeutic targeting. Video Abstract The chemotherapeutic drug etoposide induces metabolic reprogramming towards glycolysis in the NSCLC cells. The secreted lactic acid coordinates TGF-?1/Snail and TAZ/AP-1 pathway to activate the expression of MRP1/ABCC1 protein, thus contributing to chemoresistance in NSCLC.

Project description:BackgroundDue to the high incidence and mortality of lung cancer, and etoposide is the standard first-line chemotherapy for small cell lung cancer, to evaluate the efficacy and safety of etoposide capsules at different doses as maintenance therapy for patients with extensive-stage small cell lung cancer (ES-SCLC) who show a response to etoposide plus platinum.MethodsThe study was divided into two stages: stage I, a single-center, one-arm prospective study, and stage II, a multicenter, controlled non-randomized prospective study (patients were chosen from ClinicalTrials.gov Identifier: NCT02179528). All patients received six cycles of etoposide plus platinum. Patients who were evaluated as complete remission (CR) or partial remission (PR) entered the maintenance treatment (MT) (etoposide capsule, once a day for 20 days, every 28 days as a cycle, until disease progression). In stage I, the dose of etoposide was 25 mg; in stage II, patients were non-randomized into etoposide capsule (25 mg/50 mg) and observation groups. In this study, the primary endpoints were progression-free survival (PFS) and safety; the secondary endpoint was overall survival (OS). Toxicity was graded according to the Common Terminology Criteria for Adverse Events v3.0.ResultsNinety-two patients were enrolled. In stage I, the median PFS was 6.700 months (95% CI: 6.408-6.992). In stage II, the median PFS of the MT group was better than that in the NMT group (8.930 vs. 5.900 months, P=0.002). In the pooled analysis, the overall median PFS of the MT group was better than that of the NMT group (7.870 vs. 5.900 months, P=0.003). However, there was no significant difference in OS between the groups (15.030 vs. 14.330 months, P=0.813). Multivariate Cox regression analysis showed that maintenance therapy was an independent protective factor for PFS in patients with ES-SCLC.ConclusionsEtoposide capsules as maintenance therapy significantly prolonged the PFS of patients with ES-SCLC who responded to etoposide plus platinum, with acceptable tolerability.

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Two novel determinants of etoposide resistance in small cell lung cancer.

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Two novel determinants of etoposide resistance in small cell lung cancer.

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