Searchable abstracts of presentations at key conferences in endocrinology
Endocrine Abstracts (2016) 41 EP599 | DOI: 10.1530/endoabs.41.EP599

ECE2016 Eposter Presentations Endocrine tumours and neoplasia (68 abstracts)

Dual targeting of PIK3/AKT/mTOR and IGF1/KRAS/BRAF pathways in an in vitro model of ovarian cancer: strategies for cell proliferation control

Cristina de Angelis 1 , Giacomo Galdiero 2 , Claudia Pivonello 2 , Roberta Patalano 2 , Giuseppe Bifulco 3 , Attilio Di Spiezio Sardo 4 , Carlo Alviggi 3 , Giuseppe De Placido 3 , Annamaria Colao 2 & Rosario Pivonello 2

1IOS and Coleman Medicina Futura Medical Centre, Naples, Italy, Naples, Italy; 2Dipartimento di Medicina Clinica e Chirurgia, Federico II University of Naples, Naples, Italy; 3Dipartimento di Neuroscienze e Scienze riproduttive ed odontostomatologiche, Federico II University of Naples, Naples, Italy; 4Dipartimento di Sanità Pubblica, Federico II University of Naples, Naples, Italy.

Ovarian cancer (OC) is the most lethal gynecological cancer. Debulking surgery and platinum-based chemotherapy are the cornerstone of OC management; however, after a partial initial response, tumors invariably relapse. Therapeutic approaches should account for interindividual heterogeneity since OC histiotypes show distinct genetic profile. A2780 cell line has been annotated as high grade serous ovarian cancer (HGSOC); nevertheless, recent research underlined that the genetic and molecular background of these cells are much closer to the clear cell/endometrioid histiotypes, characterized by mutations in PIK3/AKT/mTOR and IGF1/KRAS/BRAF pathways, that are partially responsible for their chemoresistance. The aim of the current study was to assess the in vitro effects on cell proliferation of the mTORC1 inhibitor everolimus, the mTORC1/mTORC2 inhibitor OSI027 and the IGF1-R inhibitor OSI906, alone and in combinations, in A2780 cells. Dose-time response curves were obtained in A2780 treated for 24, 48, and 72 hours and 6 days with compounds given at concentrations from 1 μM to 1 pM. Everolimus significantly inhibited cell proliferation in a dose-time dependent manner (maximum inhibition 95%). OSI027 significantly inhibited cell proliferation at the highest concentrations of 1 μM and 100 nM (maximum inhibition 95%). OSI906 displayed a non-significant dose dependent trend in the inhibition of cell proliferation. Cells were then treated with combinations of drugs administered at intermediate concentrations: everolimus at 100 pM, 1 pM and 10 fM was combined with OSI906 at 100 nM, 10 nM and 1 nM; OSI027 and OSI906 were combined at 100 nM, 10 nM and 1 nM. All the co-treatments showed a higher inhibitory effect on cell proliferation compared to single compounds. These preliminary results suggested that the dual targeting of PIK3/AKT/mTOR and IGF1/KRAS/BRAF pathways may be a potentially effective approach to the management of OC. Additional experiments are being performed to further characterize the interplay between these pathways in OC.

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