Duvelisib is an orally active dual inhibitor of PI3K-δ and PI3K-γ in clinical 
development in hematologic malignancies (HM). To identify novel pairings for 
duvelisib in HM, it was evaluated alone and in combination with 35 compounds 
comprising a diverse panel of standard-of-care agents and emerging drugs in 
development for HM. These compounds were tested in 20 cell lines including 
diffuse large B-cell, follicular, T-cell, and mantle cell lymphomas, and 
multiple myeloma. Single agent activity was seen in fourteen cell lines, with a 
median GI50 of 0.59 μM. A scalar measure of the strength of synergistic drug 
interactions revealed a synergy hit rate of 19.3% across the matrix of drug 
combinations and cell lines. Synergy with duvelisib was prominent in lymphoma 
lines with approved and emerging drugs used to treat HM, including 
dexamethasone, ibrutinib, and the BCL-2 inhibitor venetoclax. Western blotting 
revealed that certain duvelisib-treated cell lines showed inhibition of 
phosphorylated (p) AKT at serine 473 only out to 12 hours, with mTORC2 dependent 
re-phosphorylation of pAKT evident at 24 hours. Combination with dexamethasone 
or ibrutinib, however, prevented this reactivation leading to durable inhibition 
of pAKT. The combination treatments also inhibited downstream signaling 
effectors pPRAS40 and pS6. The combination of duvelisib with dexamethasone also 
significantly reduced p-4EBP1, which controls cap dependent translation 
initiation, leading to decreased levels of c-MYC 6 hours after treatment. In 
support of the in vitro studies, in vivo xenograft studies revealed that 
duvelisib in combination with the mTOR inhibitor everolimus led to greater tumor 
growth inhibition compared to single agent administration. These data provide a 
rationale for exploring multiple combinations in the clinic and suggest that 
suppression of mTOR-driven survival signaling may be one important mechanism for 
combination synergy.