Abstract
Expression of the TUSC2/FUS1 tumor suppressor gene in TUSC2 deficient EGFR wildtype lung cancer cells increased sensitivity to erlotinib. Microarray mRNA expression analysis of TUSC2 inducible lung cancer cells treated with erlotinib uncovered defects in the response to oxidative stress suggesting that increasing reactive oxygen species (ROS) would enhance therapeutic efficacy. Addition of the thioredoxin reductase 1 inhibitor (TXNRD1) auranofin (AF) to NSCLC cells treated with combination of TUSC2 forced expression with erlotinib increased tumor cell apoptosis and inhibited colony formation. TXNRD1 overexpression rescued tumors from AF-TUSC2-erlotinib induced apoptosis. Neutralizing ROS with nordihydroguaiaretic acid (NDGA) abrogated cell death induced by AF-TUSC2-erlotinib, indicating a regulatory role for ROS in the efficacy of the three drug combination. Isobologram-based statistical analysis of this combination demonstrated superior synergism, compared with each individual treatment at lower concentrations. In NSCLC tumor xenografts, tumor growth was markedly inhibited and animal survival was prolonged over controls by AF-TUSC2-erlotinib. Microarray mRNA expression analysis uncovered oxidative stress and DNA damage gene signatures significantly upregulated by AF-TUSC2-erlotinib compared to TUSC2-erlotinib. Pathway analysis showed the highest positive z-score for the NRF2-mediated oxidative stress response. Taken together these findings show that the combination of TUSC2-erlotinib induces additional novel vulnerabilities that can be targeted with AF.
Highlights
Expression of the TUSC2/FUS1 tumor suppressor gene in TUSC2 deficient EGFR wildtype lung cancer cells increased sensitivity to erlotinib
Microarray mRNA expression analysis of TUSC2 inducible lung cancer cells treated with erlotinib uncovered defects in the response to oxidative stress suggesting that increasing reactive oxygen species (ROS) would enhance therapeutic efficacy
We recently reported that the TUSC2 gene delivered by nanovesicles combined with erlotinib inhibits lung cancer cell viability synergistically[6]
Summary
Expression of the TUSC2/FUS1 tumor suppressor gene in TUSC2 deficient EGFR wildtype lung cancer cells increased sensitivity to erlotinib. Pathway analysis showed the highest positive z-score for the NRF2-mediated oxidative stress response Taken together these findings show that the combination of TUSC2-erlotinib induces additional novel vulnerabilities that can be targeted with AF. Restoration of TUSC2 expression significantly inhibits tumor growth and progression in mouse models[4] These findings led to a Phase I clinical trial that showed safety and antitumor activity of TUSC2 nanovesicle-based systemic gene therapy administered intravenously in lung cancer patients[5]. (EGFR), synergistically inhibited tumor growth and metastases in NSCLC cells with wildtype EGFR by abrogating resistance pathways related to FGFR2 and mTOR activation[6] We hypothesized that this combination would induce novel vulnerabilities in the cancer cell. Our data support a novel conceptual model in which we identify vulnerabilities in wild type EGFR NSCLC cells following treatment with the TUSC2-erlotinib combination which we found could be targeted with the repurposed drug AF
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