The Phosphatidylinositol 3-Kinase (PI3K) Inhibitor Inavolisib Has Breast-cancer Synergy Combined With Recombinant Methioninase But Not on Normal Cells

Background/Aim: The phosphatidylinositol 3-Kinase (PI3K) pathway is thought to be oncogenic in cancers when it is mutated at various sites. However, drugs targeting this mutated pathway have had only modest efficacy. Recently, a new inhibitor targeting the PI3K pathway, inavolisib (IVB), has been developed. In the present study, we determined whether IVB is synergistic with recombinant methioninase (rMETase) on breast-cancer cells compared to normal fibroblasts. Materials and Methods: Cell viability was determined using the WST-8 cell-viability assay. The half-maximal inhibitory concentrations (IC50) of IVB and rMETase were determined on MCF-7 human breast-cancer cells compared to Hs-27 human normal fibroblasts in vitro. The efficacy of rMETase combined with IVB, at their respective IC50 values, on MCF-7 breast-cancer cells and Hs-27 normal fibroblasts was evaluated. Results: The IC50 of IVB on MCF-7 breast-cancer cells of 83 nM was significantly lower than the IC50 on Hs-27 normal fibroblasts, which was 8.8 μM. The combination of rMETase and IVB was synergistic on MCF-7 breast-cancer cells, resulting in an inhibition of 76.2%. In contrast, the combination of rMETase and IVB was not synergistic on Hs-27 normal fibroblasts. Conclusion: IVB had a very low IC50 on MCF-7 breast-cancer cells compared to Hs-27 normal fibroblasts. IVB had increased efficacy on MCF-7 breast-cancer cells when combined with rMETase, showing strong synergy. In contrast, the combination of rMETase and IVB showed no synergy on Hs-27 normal fibroblasts. Therefore, IVB in combination with rMETase has strong clinical potential for breast cancer and possibly other cancers.