E2F signature is predictive for the pancreatic adenocarcinoma clinical outcome and sensitivity to E2F inhibitors but not for the response to cytotoxic-based treatments

摘要

The main goal of this study was to find out strategies of clinical relevance to classify patients with a pancreatic ductal adenocarcinoma (PDAC) for individualized treatments. In the present study a set of 55 patient-derived xenografts (PDX) were obtained and their transcriptome were analyzed by using an Affymetrix approach. A supervised bioinformatics-based analysis let us to classify these PDX in two main groups named E2F-highly dependent and E2F-lowly dependent. Afterwards their characterization by using a Kaplan-Meier analysis demonstrated that E2F high patients survived significantly less than E2F low patients (9.5 months vs. 16.8 months; p = 0.0066). Then we tried to establish if E2F transcriptional target levels were associated to the response to cytotoxic treatments by comparing the IC50 values of E2F high and E2F low cells after gemcitabine, 5-fluorouracil, oxaliplatin, docetaxel or irinotecan treatment, and no association was found. Then we identified an E2F inhibitor compound, named ly101-4B, and we observed that E2F-higly dependent cells were more sensitive to its treatment (IC50 of 19.4 ± 1.8 µM vs. 44.1 ± 4.4 µM; p = 0.0061). In conclusion, in this work we describe an E2F target expression-based classification that could be predictive for patient outcome, but more important, for the sensitivity of tumors to the E2F inhibitors as a treatment. Finally, we can assume that phenotypic characterization, essentially by an RNA expression analysis of the PDAC, can help to predict their clinical outcome and their response to some treatments when are rationally selected.