Therapeutic benefit of selective inhibition of p110α PI3-kinase in pancreatic neuroendocrine tumors Journal Article

Authors: Soler, A.; Figueiredo, A. M.; Castel, P.; Martin, L.; Monelli, E.; Angulo-Urarte, A.; Milà-Guasch, M.; Viñals, F.; Baselga, J.; Casanovas, O.; Graupera, M.
Article Title: Therapeutic benefit of selective inhibition of p110α PI3-kinase in pancreatic neuroendocrine tumors
Abstract: Purpose: Mutations in the PI3K pathway occur in 16% of patients with pancreatic neuroendocrine tumors (PanNETs),which suggests that these tumors are an exciting setting for PI3K/AKT/mTOR pharmacologic intervention. Everolimus, an mTOR inhibitor, is being used to treat patients with advanced PanNETs. However, resistance tomTOR-targeted therapy is emerging partially due to the loss ofmTOR-dependent feedback inhibition of AKT. In contrast, the response to PI3K inhibitors in PanNETs is unknown. Experimental Design: In the current study, we assessed the frequency of PI3K pathway activation in human PanNETs and in RIP1-Tag2 mice, a preclinical tumor model of PanNETs, and we investigated the therapeutic efficacy of inhibiting PI3K in RIP1-Tag2 mice using a combination of pan (GDC-0941) and p110aselective (GDC-0326) inhibitors and isoform-specific PI3K kinase-dead-mutant mice. Results: Human and mouse PanNETs showed enhanced pAKT, pPRAS40, and pS6 positivity compared with normal tissue. Although treatment of RIP1-Tag2 mice with GDC-0941 led to reduced tumor growth with no impact on tumor vessels, the selective inactivation of the p110a PI3K isoform, either genetically or pharmacologically, reduced tumor growth as well as vascular area. Furthermore, GDC-0326 reduced the incidence of liver and lymph node metastasis compared with vehicle-treated mice. We also demonstrated that tumor and stromal cells are implicated in the antitumor activity of GDC-0326 in RIP1-Tag2 tumors. Conclusions: Our data provide a rationale for p110a-selective intervention in PanNETs and unravel a new function of this kinase in cancer biology through its role in promoting metastasis. Clin Cancer Res; 22(23); 5805-17. ©2016 American Association for Cancer Research.
Journal Title: Clinical Cancer Research
Volume: 22
Issue: 23
ISSN: 1078-0432
Publisher: American Association for Cancer Research  
Date Published: 2016-12-01
Start Page: 5805
End Page: 5817
Language: English
DOI: 10.1158/1078-0432.ccr-15-3051
PROVIDER: scopus
PUBMED: 27225693
PMCID: PMC5338478
Notes: Article -- Export Date: 3 January 2017 -- Source: Scopus
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MSK Authors
  1. Pau Castel
    19 Castel
  2. Jose T Baselga
    394 Baselga