A novel role for the tumor suppressor geneITF2in lung tumorigenesis and chemotherapy response

SUMMARYDespite often leading to platinum resistance, platinum-based chemotherapy continues to be the standard treatment for many epithelial tumors. In this study we analyze the cytogenetic alterations that arise after cisplatin treatment providing novel insights into the molecular biology and the cellular mechanisms involved in the acquired resistance in these tumor types.MethodsIn this study, we used 1 million array-CGH and qRT-PCR methodologies to identify and validate cytogenetic alterations that arise after cisplatin treatment in four lung and ovarian paired cisplatin-sensitive/resistant cell lines. We used whole transcriptome sequencing (RNA-seq), functional transfection assays and gene-pathway activity analysis in our experimental cellular models and in fresh frozen primary NSCLC tumors to identify genes with a potential role in the development of this malignancy. Results were further explored in 55 lung and ovarian primary tumors and control samples and in two extensive in silico databases (TCGA and KMplotter) with 1,926 NSCLC and 1,425 additional epithelial tumors.ResultsLong-term cell exposure to platinum induces the frequent deletion ofITF2gene. Restoration ofITF2expression re-sensitizes tumor cells to platinum and recovers the levels of Wnt/β-catenin transcriptional activity.ITF2expression was also frequently downregulated in NSCLC, ovarian and other epithelial tumors, predicting a worse overall survival. We also identified an inverse correlation in expression betweenITF2andHOXD9, revealing that NSCLC patients with lower expression ofHOXD9have a better overall survival rate that was independent of the tumor histology.ConclusionWe have defined the implication ofITF2as a molecular mechanism behind the development of cisplatin resistance probably through the activation of the Wnt-signaling pathway. Our translational data suggest thatITF2could be used as a general epithelial tumor platinum-predictive marker and have identifiedHOXD9as a potential prognostic biomarker in NSCLC, a gene which expression is induced byWntsignaling. Furthermore, this data highlights the possible role ofITF2andHOXD9as a novel therapeutic target for platinum resistant tumors.