AKT Isoforms Interplay in High-Grade Serous Ovarian Cancer Prognosis and Characterization.

Eros Azzalini,Daniela Russo,Giorgio Giorda,Domenico Tierno,Renzo Barbazza,Michele Bartoletti,Vincenzo Canzonieri,Nunzia Simona Losito,Fabio Puglisi,Serena Bonin,Sabrina Chiara Cecere,Giorgio Stanta

doi:10.3390/cancers14020304

Abstract

Simple SummaryNew therapeutical strategies are needed to improve survival in high-grade serous ovarian cancer (HGSOC) patients. AKT inhibitors are promising agents able to act in synergy with PARP inhibitors and platinum-based therapies, but the subset of patients who could benefit from this approach is still unclear. We analyzed AKT isoforms expression in a retrospective cohort and we identified four AKT expression groups related to patients’ survival, tumor morphology and the BRCA status that could help in stratifying patients for future clinical trials.High-grade serous ovarian cancer (HGSOC) is among the deadliest gynecological malignancies. The acquired resistance to platinum-based therapies and the intrinsic heterogeneity of the disease contribute to the low survival rate. To improve patients’ outcomes, new combinatorial approaches able to target different tumor vulnerabilities and enhance the efficacy of the current therapies are required. AKT inhibitors are promising antineoplastic agents able to act in synergy with PARP inhibitors, but the spectrum of patients who can benefit from this combination is unclear, since the role of the three different isoforms of AKT is still unknown. Here, we study the expression of AKT isoforms on a retrospective cohort of archive tissue by RT-droplet digital PCR (ddPCR) analyzing their association with the clinicopathological features of patients. Based on AKT1/AKT2 and AKT1/AKT3 ratios, we define four AKT classes which were related to patients’ survival, tumor morphology and BRCA1 expression. Moreover, our results show that high AKT3 expression levels were frequently associated with tumors having classic features, a low number of mitoses and the presence of psammoma bodies. Overall, our study obtains new insights on AKT isoforms and their associations with the clinicopathological features of HGSOC patients. These evidences could help to better define the subsets of patients who can benefit from AKT and PARP inhibitors therapy in future clinical trials.

Highlights

High-grade serous ovarian cancer (HGSOC) accounts for around 70% of epithelial ovarian carcinomas (EOC) and it is among the deadliest gynecological malignancies
Droplet digital PCR expression values for AKT isoforms were normalized using ACTB and HPRT1 genes according to the method described in gene expression data analysis guidelines of nSolver software
Among the 121 HGSOC samples included in the study, eighteen were discarded due to a poor RNA quality

Summary

Introduction

High-grade serous ovarian cancer (HGSOC) accounts for around 70% of epithelial ovarian carcinomas (EOC) and it is among the deadliest gynecological malignancies. HGSOC patients are typically diagnosed at a median age of 60 years with a late-stage disease often asymptomatic. The survival rate in the advanced stages is very poor, since only 30% of women survive after five years from diagnosis [2]. This high mortality rate is due to the lack of early detection and the acquired resistance to current chemotherapies, mostly platinum and taxane-based as first-line agents [3]. Given the high heterogeneity of the disease, most patients develop PARP resistance and cancer progression [5]. There’s an urgent need for developing combinatorial and personalized approaches able to contrast the tumor on different fronts and increase the efficacy of both first-line agents and PARPs inhibitors

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