The phosphoinositide-3 kinase (PI3K)-δ,γ inhibitor, duvelisib shows preclinical synergy with multiple targeted therapies in hematologic malignancies - Fig 3

<p><b>A Combination treatment of duvelisib plus dexamethasone or ibrutinib leads to sustained inhibition of pAKT</b>. Western blot analysis of DOHH2 (top) and SU-DHL-4 (bottom) treated with duvelisib (1 μM), dexamethasone (500 nM), ibrutinib (100nM) or the combination of duvelisib plus dexamethasone or ibrutinib for 6 hours or 24 hours and stained with pAKT (S473). <b>B. mTOR inhibition can suppress re-phosphorylation of pAKT.</b> SU-DHL-4 cells treated with duvelisib (1 μM), the pan-PI3K inhibitor GDC-0941(500 nM) or the ERK inhibitor SCH-772984 (500 nM) resulted in re-phosphorylation of pAKT (S473) at 24 hours, while combination with the PI3K/mTOR inhibitor PF-04691502 (500 nM) prevented re-phosphorylation of pAKT at 24 hours. <b>C. Re-phosphorylation of pAKT after duvelisib treatment is dependent on mTORC2</b>. DOHH2 (top) or SU-DHL-4 (bottom) treated with duvelisib (1 μM), mTOR1/2 inhibitor AZD-8055 (200 nM) or the mTORC1 inhibitor rapamycin (100 nM) for 1 hour (left) or following a 24 hour treatment with duvelisib (1 μM)(right). <b>D. Duvelisib combinations with dexamethasone and ibrutinib reduce activation of downstream effectors.</b> DOHH2 (top) and SU-DHL-4 (bottom) were treated with duvelisib, dexamethasone and ibrutinib as in Fig 3A. Western blot staining for downstream effectors pPRAS40 (T246), pP70S6K (T389) and pS6 (S235/236). <b>E. Combination of duvelisib with dexamethasone or ibrutinib leads to inhibition of cap-dependent translation</b>. DOHH2 (left) and SU-DHL-4 (right) treated as in Fig 3A and western blot stained for p4EBP1 (S65), c-MYC, peIF4E (s209) and cleaved PARP. The total eIF4E blots demonstrate that equal amounts of protein were loaded per lane.</p

The phosphoinositide-3 kinase (PI3K)-δ,γ inhibitor, duvelisib shows preclinical synergy with multiple targeted therapies in hematologic malignancies - Fig 1

<p><b>A. Growth inhibition (GI₅₀) of duvelisib across the panel of twenty cell lines</b>. The median GI₅₀ across the cell line panel is 0.59 μM. In six cell lines (<b>A & B</b>) with the asterisks (RL, KARPAS-299, RPMI-8226, GRANTA-519, OCI-Ly7, OPM-2), the GI₅₀ failed to reach growth Inhibition levels of greater than fifty percent. <b>B. Growth inhibition (GI₅₀) of duvelisib across the panel of twenty cell lines grouped by tumor subtype</b>. The median GI₅₀ across the cell line panel is 0.59 μM. Cell lines are grouped according to tumor subtypes: Diffuse large B cell lymphoma (DLBCL) activated B cell (ABC) and germinal center B cell (GCB), follicular lymphoma (FL), T cell lymphoma (T cell), mantle cell lymphoma (MCL) and multiple myeloma (MM).</p

Activity of duvelisib in a panel of malignant hematologic cell lines.

<p>Activity of duvelisib in a panel of malignant hematologic cell lines.</p

The phosphoinositide-3 kinase (PI3K)-δ,γ inhibitor, duvelisib shows preclinical synergy with multiple targeted therapies in hematologic malignancies - Fig 2

<p><b>A. Synergy scores for combination of duvelisib with drugs with different mechanisms of action</b>. Synergy Scores that exceed the mean self-cross plus two times the standard deviation are highlighted in purple. <b>B. Synergy score heat maps for duvelisib combined with dexamethasone, ibrutinib and venetoclax.</b> Representative heat maps for indicated combinations in the TMD-8, SUDHL-4 and DOHH2 cell lines. Scores up to 100 indicate growth inhibition while values >100 indicate cell death.</p