3091 Background: Using an in vitro dose matrix approach, we previously showed in multiple colorectal cancer cell lines a striking cytotoxic synergism between oxaliplatin at very low concentrations and the ATR inhibitor VE-822. We confirmed this finding in vivo, and, surprisingly, in this setting the oxaliplatin-induced cell addiction to VE-822 persists over several days after oxaliplatin elimination. We tried to elucidate the molecular mechanism of the latter phenomenon. Methods: We evaluated by RNAseq the gene expression changes induced in vitro by low-dose oxaliplatin in the colorectal cancer cell line HCT-116 after 24 and 48 hours of treatment. In order to untangle the functional significance of the adaptive response to oxaliplatin, we performed on the RNAseq data an extensive gene set enrichment analysis (GSEA) using gene set from all Molecular Signature Database v7.4 collections with the exception of C7. For ontology-based gene set collections, we clusterized the enriched gene sets using the semantic similarity methodology in order to increase the readability of global functional response. Results: Extensive GSEA showed that after 24 hours of oxaliplatin treatment cancer cells upregulate several gene sets involved in aspecific responses to cellular stress or to various type of extracellular stimulations, including other organisms, oxygen-containing compounds, abiotic stimuli and hypoxia. In addition, several gene sets involved in proteolysis and autophagy are upregulated, suggesting a rewiring of cell machinery. After 48 hours of oxaliplatin treatment, we observed the activation of ribosome function, mitochondrial assembly and synthesis of aminoacids and ribonucleosides. Finally, a widespread negative enrichment of gene sets involved in DNA repair-related was detected both at 24 and at 48 hours, with a far greater negative enrichment at 48 hours, which suggest a commitment of cancer cell to a major limitation of DNA repairing capability lasting several days following a DNA damaging insult. Analysis of leading edge genes from the DNA repair gene sets showed a profound repression both at 24 and 48 hours of the transcripts of BRCA1, BRCA2, ATM, CHK1, WEE1, BARD1, BRIP1, NEHJ1, RAD51, XRCC2, CLSPN, GEN1, DNA2, EXO1, TOPBP1, POLE, RMI1. Interestingly, ATR mRNA was minimally repressed both at 24 and at 48 hours, which could explain the long-standing in vivo dependence of cancer cell to ATR after a brief oxaliplatin exposure. Conclusions: Extensive GSEA was able to elucidate the molecular mechanism underlying synergistic interaction between oxaliplatin and VE-822. The impact of profiling cancer cell adaptive responses by extensive GSEA should be further evaluated in the setting of rational development of drug combinations.
e16179 Background: Biliary tract cancers (BTCs) are a group of rare tumors with a dismal prognosis and a complex molecular landscape. In this setting, the incidence and clinical relevance of cancer-associated thrombosis (CAT) is unknown, thus BTCs are not included in common thrombotic risk scores (e.g. Khorana Score). Moreover, retrospective studies highlighted associations between thromboembolic events and some genetic alterations, such as KRAS in lung and colorectal cancer, ALK/ROS1 in lung cancer and IDH1 mutations in glioma. Nevertheless, the impact of different genomic alterations on CAT risk in BTCs patients has never been investigated. The aim of this study was to investigate for the first time the incidence and the clinical relevance of CAT in a cohort of BTC patients. In addition, we investigated the association between tumor genomics and CAT in this patients’ population. Methods: Clinical and genomic data of consecutive BTC patients who underwent extensive molecular profiling with the FoundationOneCDx panel at Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Italy, were collected. The association between genomic alterations and CAT incidence was investigated with the Fisher exact test, considering alterations occurring in at least 5% of patients. Cox regression was used to analyze the impact of CAT, considered as a time-dependent covariate, on overall survival (OS). Results: 140 patients were included in the analysis, mostly represented by cases of intrahepatic cholangiocarcinoma (77%). CAT occurred in 18 (13%) patients, the majority being pulmonary embolism (28%) and visceral thrombosis (44%). Pathogenic KRAS and BRCA1 mutations were found in 33% and 11% of patients with CAT, resulting significantly associated with an increased risk of thrombosis ( p = 0.041 for both). Patients who experienced CAT showed a significantly poorer OS (HR 3.29, p = < 0.001). Conclusions: This is the first report describing a non-negligible incidence and significant prognostic impact of CAT in BTC patients. Future studies investigating the clinical and molecular risk factors for CAT in this population are needed to tailor thromboprophylaxis in this rare population.
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