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Abstract
Introduction/Background Considerable efforts have been made to understand the leading causal mechanisms behind the development of platinum resistance in relapsed High Grade Serous ovarian Cancer (HGSC). Epigenetic alterations probably play an important role in platinum-resistant disease emergence and Differentially Gene Expression Analysis (DGEA) may highlight those underlying changes.
Methodology FFPE samples from chemo naïve (diagnosis) and platinum-resistant recurrence (mainly at the time of surgery for bowel obstruction) were used to perform RNA extraction (QIAGEN RNeasy FFPE Kit). DGEA both at the general, patient, and site’s level was then performed to discover possible changes in the transcriptome (RNA sequencing) that may explain platinum-resistance development.
Results We collected 25 samples (8 patients) with at least 2 biopsies at diagnosis (ovary and peritoneal/distant site) and 2 at relapse (nodal or peritoneal). We confirmed the heterogeneity of HGSC since only 2 out of 8 patients’ biopsies clustered together at diagnosis and patients with similar gene expression at diagnosis kept their similarity at relapse (both those patients were the only two BRCA1/2 carriers). When comparing all diagnoses versus all relapses, and distant sites at diagnosis versus relapse at patient’s level, we found a consistent enrichment in the Wnt signaling pathway, while when comparing primary versus distant sites at diagnosis there was an enrichment of the PI3K-Akt pathway. All the comparisons showed an enrichment in the acute inflammatory response. Additionally, we found an enrichment in neuronal biological processes in all the mentioned analyses. These findings strengthen previous results obtained in 2-dimensions preclinical models, based on primary cell cultures.
Conclusion The discovery of novel pathways associated with chemotherapy failure holds the potential for ground-breaking therapeutic interventions. Wnt signaling and PI3K-Akt pathways may emerge as new players in the development of platinum resistance in HGSC. These promising findings open up new avenues to enhance treatment efficacy.
Disclosures R.E. reports Honoraria/consultation fees from GSK; C.M. reports Honoraria/consultation fees from AstraZeneca, Pharmamar, GSK, MSD, Menarini; A.F. reports Honoraria/consultation fees from AstraZeneca, MSD, Johnson & Johnson; G.S reports Honoraria/consultation fees from Covidien AG, AstraZeneca, MSD, Olympus Europa, Baxter Healthcare, GlaxoSmithKline, Intuitive Surgical Inc.; I.M. reports Honoraria/consultation fees from Clovis Oncology, AZ, GSK, Roche, Scancell, OncoC4, Theolytics.
