Co-Targeting the PI3K and RAS Pathways for the Treatment of Neuroendocrine Tumours

Over the last few years there has been interest in the role of the P13K/mTOR and RAS/MEK in NETs. This study was designed to evaluate the role of these pathways in NETs specifically cell proliferation and apoptosis.

The human NET cell lines BON-1, NCI-H727 and QGP-1 (somatostatinoma) were treated with either the pan-P13K inhibitor (BKM120), or dual P13K-mTOR inhibitor (BEZ235) alone or in combination with a MEK inhibitor (PD0325901). The following parameters were assessed: proliferation, apoptosis and protein expression. 

Both BKM120 and BEZ235 decreased proliferation and increased apoptosis; combination with PD0325901 significantly enhanced the antineoplastic effects of either treatment alone. In contrast, neurotensin (NT) peptide secretion was markedly stimulated with BKM120 treatment, but not BEZ235. The combination of BEZ235 + PD0325901 significantly inhibited the growth of BON xenografts without systemic toxicity.

Both BKM120 and BEZ235 effectively inhibited NET cell proliferation and stimulated apoptosis. However, inhibition of the PI3K pathway alone with BKM120 significantly stimulated NT peptide secretion; this did not occur with the dual inhibition of both PI3K and mTOR using BEZ235 suggesting that this would be a more effective treatment regimen for NETs. Moreover, the combination of BEZ235 and the MEK inhibitor PD0325901 was a safe and more effective therapy in vivo compared with single agents alone.

Source: Clinical Cancer Research