Background/Aims The therapeutic options for metastatic neuroendocrine tumors
(NETs) are limited. As PI3K signaling is often activated in NETs, we have
assessed the effects of selective PI3Kp110α inhibition by the novel agent
BYL719 on cell viability, colony formation, apoptosis, cell cycle, signaling
pathways, differentiation and secretion in pancreatic (BON-1, QGP-1) and
pulmonary (H727) NET cell lines. Methods Cell viability was investigated by
WST-1 assay, colony formation by clonogenic assay, apoptosis by caspase3/7
assay, the cell cycle by FACS, cell signaling by Western blot analysis,
expression of chromogranin A and somatostatin receptors 1/2/5 by RT-qPCR, and
chromogranin A secretion by ELISA. Results BYL719 dose-dependently decreased
cell viability and colony formation with the highest sensitivity in BON-1,
followed by H727, and lowest sensitivity in QGP-1 cells. BYL719 induced
apoptosis and G0/G1 cell cycle arrest associated with increased p27
expression. Western blots showed inhibition of PI3K downstream targets to a
varying degree in the different cell lines, but IGF1R activation. The most
sensitive BON-1 cells displayed a significant, and H727 cells a non-
significant, GSK3 inhibition after BYL719 treatment, but these effects do not
appear to be mediated through the IGF1R. In contrast, the most resistant QGP-1
cells showed no GSK3 inhibition, but a modest activation, which would
partially counteract the other anti-proliferative effects. Accordingly, BYL719
enhanced neuroendocrine differentiation with the strongest effect in BON-1,
followed by H727 cells indicated by induction of chromogranin A and
somatostatin receptor 1/2 mRNA-synthesis, but not in QGP-1 cells. In BON-1 and
QGP-1 cells, the BYL719/everolimus combination was synergistic through
simultaneous AKT/mTORC1 inhibition, and significantly increased somatostatin
receptor 2 transcription compared to each drug separately. Conclusion Our
results suggest that the agent BYL719 could be a novel therapeutic approach to
the treatment of NETs that may sensitize NET cells to somatostatin analogs,
and that if there is resistance to its action this may be overcome by
combination with everolimus
