Phosphatidylinositide 3-kinases (PI3K) are a family of lipid kinases that are involved in signaling events which control a diverse number of cellular processes. The class I PI3Ks contain 4 isoforms designated p110a, b, d, g, and are activated by cell surface receptors. Aberrant regulation of the PI3K signaling pathway is frequently observed in a wide range of human malignancies including those of hematological origin and has been shown to play an important role in tumor progression. GS-9820 is a highly selective and potent p110d inhibitor (IC50 of 14 nM) with 114- to 400-fold selectivity over the other class I PI3K enzymes and no activity against Class II and III PI3K family members or other PI3K-related proteins including mTOR and DNA-PK. Although a role for PI3Kd has been shown in multiple myeloma (MM), GS-9820 has not been previously evaluated in combination with anti-MM agents in primary MM tumor cells. Hence, we determined the effects of GS-9820 as a single agent and in combination with melphalan, dexamethasone, doxorubicin, or bortezomib on primary MM cells. GS9820 alone inhibited MM tumor cell proliferation in a concentration-dependent fashion with a 50% growth inhibition (IC50) of primary MM cells between 1–10 μM. Notably, combinations of GS-9820 (100nM-1μM) and melphalan (10 μM) or dexamethasone (1 μM) significantly decreased cellular proliferation (P < 0.05), compared to either drug alone in all 6 MM BMMC samples. GS-9820 was synergistic when combined with doxorubicin on primary MM cells from two of these patients' samples. Similarly, this PI3K inhibitor synergized when it was combined with bortezomib on primary MM cells from two of these patients. Using our LAGk-2 human tumor xenograft model, the combination of GS-9820 and melphalan provided greater growth inhibition than the individual drugs alone. Specifically on day 42 post-tumor implantation, LAGk-2-bearing mice treated with single agent GS-9820 did not show a significant reduction in tumor growth compared to vehicle-treated mice. In contrast, melphalan alone resulted in a significant decrease in tumor size when compared to vehicle-treated mice at this same time point (P = 0.0302). Importantly, the combination of GS-9820 plus melphalan resulted in statistically significantly smaller tumors when compared to melphalan alone (P = 0.0495), GS-9820 alone (P = 0.0061) and vehicle-control (P = 0.0025). In this study, we demonstrate that the combination of GS-9820 with melphalan or dexamethasone markedly inhibits primary MM cell proliferation in vitro. Furthermore, the combination of GS-9820 and melphalan shows enhanced anti-MM effects compared to single agent treatment in vivo using theLAGk-2 human xenograft MM model. The results from these studies suggest that the combination of the PI3K inhibitor, GS-9820, and other anti-MM drugs may be an effective treatment for MM patients.
Johnson:Gilead Sciences: Employment. Lannutti:Gilead Sciences: Employment.
Asterisk with author names denotes non-ASH members.