Abstract
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.
Highlights
Phosphoinositide-3 kinases (PI3Ks) are members of a unique and conserved family of intracellular lipid kinases that phosphorylate the 3’-OH group on phosphatidylinositols or phosphoinositides
To determine the direct effect of duvelisib on malignant hematologic cells, the growth inhibitory activity of duvelisib was evaluated across a panel of 20 cell lines including those derived from diffuse large B-cell lymphoma, transformed follicular lymphoma, mantle cell lymphoma, multiple myeloma, and T-cell lymphoma
Maximal growth inhibition (GI) values between 0% and 100% are indicative of a cytostatic effect on growth for duvelisib, whereas, values greater than 100% are indicative of a cytotoxic effect of the drug
Summary
Phosphoinositide-3 kinases (PI3Ks) are members of a unique and conserved family of intracellular lipid kinases that phosphorylate the 3’-OH group on phosphatidylinositols or phosphoinositides. To investigate the hypothesis that simultaneous inhibition of these isoforms would demonstrate anti-tumor growth effects in hematologic malignancies, we developed duvelisib (IPI-145), an orally active, potent dual inhibitor of both PI3K-δ and PI3K- [16]. To gain mechanistic insights into the cellular response to duvelisib and identify novel pairings for duvelisib in hematologic malignancies, a high-throughput combination screen in malignant lymphoid cell lines was conducted with a variety of standard-of-care and experimental agents important in lymphoma therapy. Relevant agents were identified that synergized with duvelisib to inhibit growth in DLBCL and transformed follicular lymphoma cell lines, and in vitro analysis revealed a potential mechanism by which these tumor types establish resistance to duvelisib monotherapy through activation of the mTOR pathway
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