Abstract 243: Overcoming resistance to cisplatin in NSCLC cell lines: TRAIL-modulating strategy by a DR5 agonist, LBY135
Authors: Caetano Mauricio S. , Sternberg Cinthya , Ferreira Carlos G. 
Published: August 2012

Abstract
Non-small-cell lung cancer (NSCLC) accounts for 80% of the lung cancer cases and is further divided into three different histological subtypes: Adenocarcinoma (ADE), Large Cell Carcinoma (LCC) and Squamous Cell Carcinoma (SCC). Treatment includes complete surgical resection, but most of the patients are already in advanced or metastatic disease stage at diagnosis. Therefore, the therapy of choice in these cases is platinum-based chemotherapy, which presents high general toxicity and stumble into an intrinsic feature of lung cancer, the high rate of chemo-resistance. The mechanisms underlying platinum resistance and sensitivity are not fully understood, and there are no validated biomarkers to select sensitive patients up to now.In spite of the recent developments in the field of target-drugs (e.g. Tyrosine kinase inhibitors), several sub-groups of lung cancer patients still have unmet needs for therapy and drugs with specific mechanisms emerge as a rational alternative. Aberrations found in the apoptotic pathway are a common feature in lung cancer. TNF-related apoptosis-inducing ligand (TRAIL) is a member of the TNF family of cytokines, which can induce apoptotic cell death in a variety of tumor cells by engaging specific death receptors, DR4 and DR5, while having low toxicity towards normal cells, which express decoy receptors for this cytokine. In this study, we sought to explore TRAIL pathway activation as a strategy to subvert the resistance to cisplatin presented by NSCLC cell lines. We have used a panel of NSCLC cell lines harboring different mutations and displaying distinct histology profiles (A549 - ADE: KRAS mut, TPp53 WT and BRAF WT; LC319 - ADE: KRAS mut, TPp53 mut and BRAF mut; H460 - LCC: KRAS mut, TPp53 WT and BRAF WT; Calu-1: SCC: KRAS mut, TPp53 null and BRAF WT. As expected, these cell lines display differential sensitivity to cisplatin. NSCLC cell lines were treated with suboptimal concentrations of cisplatin (IC30) for 48h and expression of TRAIL receptor family was accessed by real-time PCR. Our results demonstrate that IC30 of Cisplatin induces an increase in the expression of DR4 and DR5 in NSCLC cell lines, accompanied by an increase in protein expression. Also, Decoy receptors 1 and 2 (DcR1/DcR2) were differentially upregulated by cisplatin. LBY135 (Novartis) is a monoclonal Ab agonist to DR5 and it was able to decrease metabolic activity measured by MTT assay in NSCLC cell lines. We postulated that cisplatin could chemo-sensitize lung cancer cells to DR5-induced cell death. Accordingly, the combination of a Cisplatin IC30 with LBY135 had synergistic effect upon cell death in NSCLC cell lines, in spite of the fact that DcR1/2 were upregulated. Our results suggest an alternative way to subvert chemo-resistance in lung cancer, and that anti-DR5 therapies might be more effective than TRAIL-based ones, since it bypasses the DcR1/2 inhibitory effect.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 243. doi:1538-7445.AM2012-243