Targeting aurora kinases with danusertib (PHA-739358) inhibits growth of liver metastases from gastroenteropancreatic neuroendocrine tumors in an orthotopic xenograft model

Purpose: Aurora kinases play a crucial role in cell-cycle control. Uncontrolled expression of aurora kinases causes aneuploidy and tumor growth. As conservative treatment options for advanced gastroenteropancreatic neuroendocrine tumors (GEP-NET) are disappointing, aurora kinases may be an interesting target for novel therapeutic strategies.

Experimental design: Human GEP-NETs were tested for Aurora Kinase expression. The efficacy of the new Aurora Kinase Inhibitor danusertib was evaluated in two human GEP-NET cell lines (BON1 and QGP) in vitro and in vivo.

Results: The majority of ten insulinomas and all 33 nonfunctional pancreatic or midgut GEP-NETs expressed Aurora A despite a mostly high degree of cell differentiation. Both human GEP-NET cell lines expressed Aurora Kinase A and B, and high Ser10 phosphorylation of histone H3 revealed increased Aurora B activity. Remarkably, danusertib led to cell-cycle arrest and completely inhibited cell proliferation of the GEP-NET cells in vitro. Decreased phosphorylation of histone H3 indicated effective Aurora B inhibition. In a subcutaneous murine xenograft model, danusertib significantly reduced tumor growth in vivo compared with controls or mice treated with streptozotocine/5-fluorouracil. As a consequence, decreased levels of tumor marker chromogranin A were found in mouse serum samples. In a newly developed orthotopic model for GEP-NET liver metastases by intrasplenic tumor cell transplantation, dynamic MRI proved significant growth inhibition of BON1- and QGP-derived liver metastases.

Conclusions: These results show that danusertib may impose a new therapeutic strategy for Aurora Kinase expressing metastasized GEP-NETs.