Impact of phospho-Akt expression on the clinical outcome and activity of gemcitabine and Akt inhibitors in pancreatic ductal adenocarcinoma

Alessandro Perez, Valentina Calo', Antonio Galvano, Aurelia Ada Guarini, Daniela Massihnia, Antonio Russo, Nadia Barraco, Francesco Passiglia, Angela Listi', Leticia G. Leon, Russo, Antonio Galvano, Marta Castiglia, Francesco Passiglia, Listì, Barraco, Daniela Massihnia, Perez, Guarini, CastellanaNiccola Funel, Elisa Giovannetti, Calò, Sergio Rizzo, Luisa Castellana

Risultato della ricerca: Meeting Abstract

Abstract

Background: Pancreatic ductal adenocarcinoma (PDAC) is among the most lethalsolid tumors. Despite extensive preclinical and clinical research, the prognosis of thisdisease has not significantly improved, with a 5-year survival rate around 7%. There isan urgent need to better understand the molecular pathology of PDAC in order toimprove patient selection for current treatment options and to develop novel therapeutic strategies. The PI3K/AKT/mTOR pathway plays a crucial role in PDAC: activationof Akt is a frequent event and has been correlated to poor prognosis and resistance tochemotherapy. Against this background, effective blockage of Akt signaling can lead toprogrammed cell death and inhibition of tumor growth. Several inhibitors of Akt underinvestigation include perifosine, which prevents Akt translocation to the cell membrane, MK-2206 which is an Akt allosteric inhibitor and BEZ-235 which is a dual PI3K/mTOR inhibitor. The aims of this study were to investigate 1) the prognostic role ofAkt in PDAC tissues and 2) the molecular mechanisms underlying the interaction ofAkt inhibitors with gemcitabine in PDAC cells and primary cultures.Materials and methods: Immunohistochemistry of tissue microarrays with specimensfrom radically-resected patients (n ¼ 100) revealed a correlation between high phospho-Akt1 expression and worse outcome. Patients with low expression had a medianoverall survival (OS) of 16.2 months (95%CI, 14.8-20.1), while patients with highexpression had a median OS of 12.0 months (95%CI, 9.0-14.9, P ¼ 0.03).Results: Akt inhibitors synergistically enhanced the antiproliferative activity of gemcitabine in the LPC028 primary cells, characterized by high expression levels, while thiscombination was antagonistic in LPC006 cells, characterized by low expression levels.Inhibition of Akt decreased cell migration and invasion, which was additionallyreduced by the combination with gemcitabine. However, the combination of Aktinhibitors with gemcitabine significantly increased apoptosis, associated with induction of caspase-3/6/8/9, PARP and BAD, and inhibition of Bcl-2 and NF-kB in LPC028,but not in LPC006 cells.Conclusions: Our results support the analysis of phospho-Akt as a new biomarkerboth for PDAC prognosis and for the development of new therapeutic approaches. Inparticular, perifosine interact synergistically with gemcitabine in cells with phosphoAkt overexpression
Lingua originaleEnglish
pagine (da-a)vi45-vi45
Numero di pagine1
RivistaAnnals of Oncology
Volume28
Stato di pubblicazionePublished - 2017

All Science Journal Classification (ASJC) codes

  • Hematology
  • Oncology

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