Novel phosphatidylinositol 3-kinase inhibitor BKM120 enhances the sensitivity of multiple myeloma to bortezomib and overcomes resistance

Abstract

Proteasome inhibitor bortezomib has proven efficacy against multiple myeloma. However, bortezomib activates the phosphatidylinositol 3-kinase/AKT (PI3K/AKT) pathway (which is essential to the development of myeloma), often resulting in drug resistance and disease recurrence. The addition of BKM120 significantly enhanced the apoptotic effects of bortezomib in both bortezomib-sensitive and bortezomib-resistant cells. Treatment with bortezomib alone increased the phosphorylation of AKT (P-AKT), whereas the addition of BKM120 markedly downregulated P-AKT in both bortezomib-sensitive and bortezomib-resistant cells. The clinical relevance of combined treatment with bortezomib and BKM120 was investigated in a xenograft mouse model and in myeloma patients, and the synergy of the combination was confirmed. In conclusion, the addition of BKM120 enhanced the sensitivity of myeloma cells to bortezomib.

Keywords: BKM120; bortezomib; drug resistance; mouse model; multiple myeloma cells.