Abstract:
:Introduction Dysregulation of the mTORC1-dependent pathways in pancreatic neuroendocrine neoplasms (PanNENs) underlies the introduction of the mTORC1 inhibitor everolimus as treatment of advanced progressive PanNENs. Although everolimus significantly increases progression free survival, most patients acquire secondary resistance to the drug. This study aimed at identifying mechanisms involved in acquisition of resistance to everolimus. Methods BON-1 and everolimus-resistant (ER) BON-1 cells were used as in vitro system of sensitivity and acquired resistance. Transcriptome changes occurring in BON-1 and ER-BON-1 were investigated by RNA sequencing and validated by quantitative PCR analysis. RNA extracted from patients' biopsies was used to validate MYC up-regulation. Drug screening and functional assays were performed using ER-BON-1 cells. Cell cycle progression was evaluated by FACS analysis. Results Our results show that MYC overexpression is a key event in the development of secondary resistance to everolimus in PanNENs cell lines and in metastatic lesions from NEN patients. MYC knock-down restored ER-BON-1 sensitivity to everolimus. Pharmacological inhibition of MYC mediated by the cyclin-dependent kinase inhibitor Dinaciclib strongly reduced viability of ER-BON-1. Dinaciclib synergized with everolimus and inhibited ER-BON-1 cell cycle progression. Discussion Our findings suggest that MYC up-regulation drives the development of secondary resistance to everolimus in PanNENs and that its inhibition is an exploitable vulnerability. Indeed, our results indicate that combined treatments with cyclin-dependent kinase and mTOR inhibitors may counteract secondary resistance to everolimus in PanNENs and may pave the ground for new therapeutic regimens for these tumors.
journal_name
Neuroendocrinologyjournal_title
Neuroendocrinologyauthors
Terracciano F,Capone A,Montori A,Rinzivillo M,Partelli S,Panzuto F,Pilozzi E,Arcidiacono PG,Sette C,Capurso Gdoi
10.1159/000509865subject
Has Abstractpub_date
2020-07-02 00:00:00eissn
0028-3835issn
1423-0194pii
000509865pub_type
杂志文章abstract::Immunoreactive thyroid-stimulating hormone (IR-TSH) has been detected in the hypothalamus and is released in vitro by a calcium-dependent mechanism when the tissue is depolarized. Recently, immunocytochemical studies have revealed that IR-TSH is present in thyrotropes in the pars tuberalis. Therefore, because these th...
journal_title:Neuroendocrinology
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pub_type: 临床试验,杂志文章,随机对照试验
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更新日期:2008-01-01 00:00:00
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journal_title:Neuroendocrinology
pub_type: 杂志文章
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更新日期:2020-06-03 00:00:00
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更新日期:1995-04-01 00:00:00
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journal_title:Neuroendocrinology
pub_type: 杂志文章
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更新日期:1989-06-01 00:00:00
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pub_type: 杂志文章
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更新日期:2004-01-01 00:00:00
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journal_title:Neuroendocrinology
pub_type: 杂志文章,评审
doi:10.1159/000335018
更新日期:2013-01-01 00:00:00