Inhibition of cell cycle progression by dual phosphatidylinositol-3-kinase and mTOR blockade in cyclin D2 positive multiple myeloma bearing IgH translocations

Multiple myeloma (MM) is a clinically and genetically heterogenous cancer where tumour cells have dysregulated expression of a D-type cyclin, often in association with a recurrent IgH translocation. Patients whose tumour cells express cyclin D2, with the translocation t(4;14) or t(14; 16), generally have more proliferative disease and inferior outcomes. The phosphatidylinositol-3-kinase (PI3K) pathway is a major regulator of D-type cyclin expression and cell cycle entry. We evaluated the effect of PI3K pathway blockade on cell cycle behaviour in MM cells, investigating differences between cyclin D2- and cyclin D1-expressing tumours. MM cell lines and primary bone marrow CD138(+) MM cells were exposed to the pan-PI3K/mTOR inhibitor, PI-103, and assessed for cell cycle profiles, [H-3]-thymidine uptake and cell cycle proteins. We report, in both cell lines and primary MM cells, that PI-103 induced cell cycle arrest with downregulation of cyclin D2 and CDK4/6 in MM cells expressing cyclin D2 via t(4; 14) or t(14; 16) translocations. Cells expressing cyclin D1 via t(11; 14) were insensitive to PI-103, despite exhibiting inhibition of downstream signalling targets. In primary MM cells, PI-103 enhanced the anti-proliferative effects of anti-MM agents. Treatment paradigms including blockade of the PI3K/mTOR pathway should be targeted at patients with IgH translocations associated with cyclin D2 overexpression.