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

Abstract

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.

Nanomechanical Characterization of Ovarian Cancer Cell Lines as a Marker of Response to 2c Treatment

“…As ubiquitin-specific peptidase 5 has been shown to promote ovarian cancer cell proliferation, 2c can represent a possible new treatment for EOC [ 30 ]. The possible utility of 2c in ovarian cancer can also be related to its activity on AKT molecules [ 29 ], which have already been related to patients’ survival, tumor morphology and BRCA1 expression [ 31 ]. Accordingly, our data obtained by droplet digital PCR analysis returned higher expression levels of the AKT3 gene in bimodal cell lines compared to the unimodal ones, further stressing the role of AKT isoforms in mediating the resistance to therapy.…”

“…For a limited number of genes (AKT1, AKT2, AKT3, PI3KCB, PTEN, HER2, CCNE1, RB1, CDK2), the expression analysis was performed by RT-ddPCR using 1 ng of cDNA. RT-ddPCR analyses were carried out as already reported [ 31 ], with the difference that RT reaction was carried out using oligo dT priming. PCR conditions as well as primer sequences can be retrieved in previously published reports [ 31 , 48 ].…”

“…RT-ddPCR analyses were carried out as already reported [ 31 ], with the difference that RT reaction was carried out using oligo dT priming. PCR conditions as well as primer sequences can be retrieved in previously published reports [ 31 , 48 ]. Data were normalized against the expression level of 3 housekeeping genes, namely HPRT1, HMBS and PPIB.…”

Quantifying mRNA in Highly Degraded Fixed Tissues by Nanostring Technology: A Comparative Study

“…Fixation and embedding procedures were routinely performed in the laboratory during the patient’s surgery. The case series has already been used in previous studies [ 3 , 8 ].…”

Akt Inhibitor Advancements: From Capivasertib Approval to Covalent-Allosteric Promises

“…CAAIs, with their covalent MOA, are an innovative approach to tackle the aforementioned selectivity issues. It is worth noting that the distinctive role of each Akt isoform is not completely understood. − Evidence suggests hyperactivation of certain Akt isoforms in particular tumors, indicating Akt isoform-specificity in cell transformation. This specificity may arise from gene-dependent or -independent Akt isoform amplification .…”