Simultaneous Inhibition of PI3Kδ and PI3Kα Induces ABC-DLBCL Regression by Blocking BCR-Dependent and -Independent Activation of NF-κB and AKT

Paul, Juliane; Soujon, Maurice; Wengner, Antje M.; Zitzmann-Kolbe, Sabine; Sturz, Andrea; Haike, Katja; Magdalene, Koh Hui Keng; Tan, Sze Huey; Lange, Martin; Tan, Soo Yong; Mumberg, Dominik; Lim, Soon Thye; Ziegelbauer, Karl; Liu, Ningshu

doi:10.1016/j.ccell.2016.12.003

Cited by 127 publications

(121 citation statements)

References 38 publications

(51 reference statements)

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“…In particular, the cell lines derived from MCL and ABC DLBCL presented reduction of p‐AKT and increased cytotoxicity. The benefit of the combination observed in our lymphoma models is in agreement with that observed in CLL models using the same compounds (Niemann et al , ), and also supported by data obtained using different BTK and PI3K inhibitors (Mathews Griner et al , ; Paul et al , ; Yahiaoui et al , ; Faia et al , ; Schaffer et al , ; Tarantelli et al , ; Tarantelli et al , ). Both sets of data support an on‐going clinical study (NCT02328014), which has shown positive signals of activity, especially in ABC DLBCL (Barr et al , ).…”

Section: Discussionsupporting

confidence: 90%

Single and combined BTK and PI3Kδ inhibition with acalabrutinib and ACP‐319 in pre‐clinical models of aggressive lymphomas

et al. 2019

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Summary The B‐cell receptor and the phosphatidylinositol 3‐kinase (PI3K) signalling pathways, together with their downstream partners, represent important therapeutic targets for B‐cell lymphomas. Here, we evaluated the activity of acalabrutinib (ACP‐196) and ACP‐319 (AMG‐319), second generation inhibitors of Bruton tyrosine kinase (BTK) and PI3Kδ inhibitor, respectively, in lymphoma pre‐clinical models. The two compounds showed activity in activated B‐cell‐like diffuse large B‐cell lymphoma (ABC DLBCL), mantle cell lymphoma and marginal zone lymphoma. Two in vivo experiments with ABC DLBCL and MCL xenografts confirmed the effect of the single agents. Benefit was achieved by exposing the lymphoma cell lines to both acalabrutinib and ACP‐319. Two cell lines presented a discordant response to first and second generation BTK inhibitors, probably due to the inhibition by ibrutinib of kinases other than BTK. In conclusion, our data sustain the on‐going current trials with acalabrutinib and ACP‐319 as single agents and provide the basis for the investigation of their combination as well.

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Section: Discussionsupporting

confidence: 90%

Single and combined BTK and PI3Kδ inhibition with acalabrutinib and ACP‐319 in pre‐clinical models of aggressive lymphomas

et al. 2019

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“…Direct measurement of BTK occupancy in CSF, if technically feasible, might provide further insight into this important question. Combination therapy of ibrutinib with inhibitors of p110α/p110δ PI3K or mTOR, which are in advanced stages of clinical testing, may offer a strategy to augment the depth and duration of ibrutinib responses in CD79B -mutant PCNSL and perhaps other DLBCL subgroups (46). Further studies are needed to evaluate if second generation BTK inhibitors with different pharmacokinetic properties and kinase selectivity might augment the remarkable clinical activity of ibrutinib in CNS lymphoma.…”

Section: Discussionmentioning

confidence: 99%

Ibrutinib Unmasks Critical Role of Bruton Tyrosine Kinase in Primary CNS Lymphoma

et al. 2017

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Bruton tyrosine kinase (BTK) links the B-cell antigen receptor (BCR) and Toll-like receptors with Nuclear factor kappa B (NF-κB). The role of BTK in primary CNS lymphoma (PCNSL) is unknown. We performed a Phase 1 clinical trial with ibrutinib, the first-in-class BTK inhibitor, for patients with relapsed or refractory CNS Lymphoma. Clinical responses to ibrutinib occurred in 10/13 (77%) PCNSL patients, including five complete responses. The only PCNSL with complete ibrutinib resistance harbored a mutation within the coiled-coil domain of Caspase Recruitment Domain Family Member 11, a known ibrutinib resistance mechanism. Incomplete tumor responses were associated with mutations in the B-Cell Antigen Receptor-associated protein CD79B. CD79B-mutant PCNSLs showed enrichment of mammalian target of rapamycin (mTOR)-related gene sets and increased staining with Phosphatidylinositol 3-kinase (PI3K)/mTOR activation markers. Inhibition of the PI3K-isoforms p110α/p110δ or mTOR synergized with ibrutinib to induce cell death in CD79B-mutant PCNSL cells.

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“…Combination strategies will be critical for better management of PDAC as well as other tumors. In diffuse large B-cell lymphoma, activation of AKT and BTK signaling followed monotherapy treatment with BTK inhibitor ibrutinib and PI3Kα/δ inhibitor copanlisib led to striking improvement in efficacy (14). Cross-resistance to BRAF and MEK inhibitors in melanoma can be overcome with PI3K pathway targeting (15).…”

Section: Introductionmentioning

confidence: 99%

Combinatorial Screening of Pancreatic Adenocarcinoma Reveals Sensitivity to Drug Combinations Including Bromodomain Inhibitor Plus Neddylation Inhibitor

Langdon

Platt

Means

et al. 2017

Molecular Cancer Therapeutics

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Pancreatic adenocarcinoma (PDAC) is the fourth most common cause of cancer death in the United States. PDAC is difficult to manage effectively, with a five-year survival rate of only 5%. PDAC is largely driven by activating KRAS mutations, and as such, cannot be directly targeted with therapeutic agents that affect the activated protein. Instead, inhibition of downstream signaling and other targets will be necessary to effectively manage PDAC. Here, we describe a tiered single-agent and combination compound screen to identify targeted agents that impair growth of a panel of PDAC cell lines. Several of the combinations identified from the screen were further validated for efficacy and mechanism. Combination of the bromodomain inhibitor JQ1 and the neddylation inhibitor MLN4294 altered production of reactive oxygen species in PDAC cells, ultimately leading to defects in the DNA damage response. Dual bromodomain/neddylation blockade inhibited in vivo growth of PDAC cell line xenografts. Overall, this work revealed novel combinatorial regimens, including JQ1 plus MLN4294, which show promise for the treatment of RAS-driven PDAC.

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Simultaneous Inhibition of PI3Kδ and PI3Kα Induces ABC-DLBCL Regression by Blocking BCR-Dependent and -Independent Activation of NF-κB and AKT

Cited by 127 publications

References 38 publications

Single and combined BTK and PI3Kδ inhibition with acalabrutinib and ACP‐319 in pre‐clinical models of aggressive lymphomas

Single and combined BTK and PI3Kδ inhibition with acalabrutinib and ACP‐319 in pre‐clinical models of aggressive lymphomas

Ibrutinib Unmasks Critical Role of Bruton Tyrosine Kinase in Primary CNS Lymphoma

Combinatorial Screening of Pancreatic Adenocarcinoma Reveals Sensitivity to Drug Combinations Including Bromodomain Inhibitor Plus Neddylation Inhibitor

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