IOA-244, a novel p110δ PI3K inhibitor, blocks breast tumour progression on either mono- or combined-therapy.

The clinical approval of p110δ PI3K inhibitors raised hopes in treating aggressive tumours expressing high levels of non-mutated p110δ, however, the severe adverse effects that those inhibitors caused became a barrier to their clinical application. IOA-244 is the first-in-class, highly selective and non-ATP competitive p110δ PI3K inhibitor showing high selectivity and low toxicity in several preclinical models. Here we show that IOA-244, as a single agent treatment, blocks the progression of early phase breast tumours by attacking the survival of cancer cells and the polarisation of TAMs to a pro-tumourigenic phenotype leading to suppression of TAMs-expressed ATX. In established tumours, IOA-244 alone was insufficient to control the high levels of both M2-like macrophages and ATX, and while it reduced tumour progression, it did not completely block it. Full tumour control, however, was achieved when IOA-244 used in a combinatorial regimen with the PF-8380 ATX inhibitor. In agreement with the mouse model, the amount of CD163+/CD204+macrophages and ATX were much higher in grade III human breast carcinomas compared to grade I. Our work provides the first in vivo preclinical evidence showing that IOA-244 is a potential highly effective drug for breast cancer treatment and depending on the phase of the tumour can be used either as a single agent or as a combinatorial regimen.