Targeting β-catenin signaling for therapeutic intervention in MEN1-deficient pancreatic neuroendocrine tumours

Abstract

Inactivating MEN1 mutations are the most common genetic defects present in sporadic and inherited pancreatic neuroendocrine tumours (PNETs). The lack of interventional therapies prompts us to explore the therapeutic approach of targeting β-catenin signalling in MEN1-mutant PNETs. Here we show the MEN1-encoded scaffold protein menin regulates phosphorylation of β-catenin. β-catenin signalling is activated in MEN1-mutant human and mouse PNETs. Conditional knockout of β-catenin suppresses the tumorigenesis and growth of Men1-deficient PNETs, and significantly prolongs the survival time in mice. Suppression of β-catenin signalling by genetic ablation or a molecular antagonist inhibits the expression of proproliferative genes in menin-null PNETs and potently improves hyperinsulinemia and hypoglycemia in mice. Blockade of β-catenin has no adverse effect on physiological function of pancreatic β-cells. Our data demonstrate that β-catenin signalling is an effective therapeutic target for MEN1-mutant PNETs. Our findings may contribute to individualized and combined medication treatment for PNETs.

The future: genetics advances in MEN1 therapeutic approaches and management strategies

“…These mouse models have shown that the expression of activated K-RAS(p.G12D) enhances rather than inhibits β-cell proliferation, β-catenin loss can suppress insulinoma tumorigenesis, histone demethylase retinoblastoma binding protein-2 (Rbp2) loss decreases insulinoma formation and prolongs survival, ActivinB loss prolongs survival, and MLL1/KMT2A loss leads to earlier onset of tumor formation (4 months vs. 6 months) and shortened lifespan by promoting tumor progression and angiogenesis (Chamberlain, et al 2014; Jiang, et al 2014; Lin, et al 2011; Lin, et al 2016; Ripoche, et al 2015). Such studies have dual benefits as they help to understand tumorigenesis and to reveal β-cell proliferation mechanisms for developing β-cell replacement strategies to help diabetic patients who suffer from functional β-cell loss (Garcia-Ocana and Stewart 2014).…”

“…Other potential treatment options targeted receptors associated with tumor angiogenesis (VEGF receptors) or specific somatostatin receptors. These pre-clinical studies include menin replacement therapy, an angiogenesis inhibitor (anti-VEGF-A monoclonal antibody, mAb G6–31), a small molecular tyrosine kinase inhibitor of all VEGF receptors (Sunitinib), a somatostatin analog (Pasireotide/SOM230), a Hedgehog pathway inhibitor GDC-0449, a β-catenin inhibitor PKF115–584, and an epigenetic drug (BET protein inhibitor JQ1) (Gurung, et al 2013b; Jiang et al 2014; Korsisaari, et al 2008; Lines, et al 2017; Quinn, et al 2012; Walls, et al 2012; Walls, et al 2016). …”

GEP- NETS UPDATE: Genetics of neuroendocrine tumors

“…Ongoing research is currently investigating whether specific RET mutations could predict the success of treatment with receptor kinase inhibitors (NCT01945762) in MTC. Another hypothesis that needs to be tested is that mutations in genes involved in mTOR signaling could be used as biomarkers of rapalogue response (155,156).development of future therapies: both combination therapy with FAK and mTOR inhibitors (157) as well as inhibition of B-catenin in MEN1 deficient pancreatic NETs (158). Immunotherapy is also an emerging branch in cancer treatment where the knowledge of tumor genetics and biology has proved to be important for prediction.…”

Epigenetic regulation by the menin pathway

“…Conditional knockout of β-catenin in Men1 -deficient mice leads to suppression of tumorigenesis and significantly improved hypoglycemia and the survival rate of the mice (Jiang, et al 2014). Antagonizing β-catenin signaling by the small molecule inhibitor PKF115–584 in Men1 -deficient mice also suppresses tumor cell proliferation in vitro and in vivo (Jiang et al 2014).…”