Optimal induction of myeloma cell death requires dual blockade of phosphoinositide 3-kinase and mTOR signalling and is determined by translocation subtype

Abstract

Novel inhibitors of PI3K, Akt and mTOR have been developed recently, some of which have entered clinical trials. Although such compounds inhibit cell proliferation, their effects on cell survival, an important determinant of clinical response, are less clear-cut. Using a broad panel of myeloma cell lines and primary patient samples we show that dual PI3K and mTOR inhibition can induce cell death. The effects are most marked in cells expressing the t(4;14) translocation, whereas t(11;14) cells are largely resistant. Using specific inhibitors of individual pathway components, we show that optimal induction of cell death requires inhibition of both PI3K and mTOR. This is due to a PI3K-independent component of mTOR activation downstream of the MAP Kinase pathway. Novel mTOR kinase inhibitors, which block both TORC1 and TORC2 complexes thereby also reducing Akt activity, are less effective than dual PI3K/mTOR inhibitors because of feedback activation of PI3K signalling. Dual PI3K/mTOR inhibitors sensitise t(4;14) and t(14;16), but not t(11;14), expressing cells to the cytotoxic effects of dexamethasone. We have identified a robust cytogenetic biomarker for response to PI3K/mTOR inhibition - these results will inform the design and prioritisation of clinical studies with novel inhibitors in genetic subgroups of myeloma.

Novel therapeutic strategies for multiple myeloma

“…While these drugs inhibit only mTORC1 and lead to activation of Akt due to negative feedback of mTORC2 [77], dual inhibition of mTORC1 and mTORC2 in MM cells demonstrates significant growth inhibition [78]. Moreover, dual inhibition of PI3K/mTOR or insulin-like growth factor 1 receptor (IGF1R)/mTOR also triggers significant anti-tumor effects in MM [79, 80]. …”

Combined targeting of MEK/MAPK and PI3K/Akt signalling in multiple myeloma

“…That this seems nevertheless to be the case would support the notion that the PI3K to Akt axis is still the most relevant signalling route for MM cell survival, and that therefore the clinically best suitable inhibitor could be chosen to complement MEK inhibition. This similarity is possibly due to the use of the dual PI3K/mTOR inhibitor PI103, because this class of drug appears to be more efficient at MM cell apoptosis induction than exclusive inhibitors of PI3K (Stengel et al , ). Notably, the MM cell line AMO‐1 explicitly did not conform to this rule of thumb, being considerably more sensitive to the combination of MEK/PI3K(mTOR) inhibitor than to MEK/Akt blockade.…”

Multifaceted roles of GSK-3 and Wnt/β-catenin in hematopoiesis and leukemogenesis: opportunities for therapeutic intervention

“…52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68 GSK-3 has complex interactions with these pathways. Some of the interactions of GSK-3 and the PI3K/PTEN/Akt/mTORC1 and Ras/Raf/MEK/ERK pathways are presented in Figure 1.…”