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Synergistic Targeting of the Regulatory and Catalytic Subunits of Pi3kd in Mature B-Cell Malignancies Jeffrey D

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Synergistic Targeting of the Regulatory and Catalytic Subunits of Pi3kd in Mature B-Cell Malignancies Jeffrey D Published OnlineFirst December 15, 2017; DOI: 10.1158/1078-0432.CCR-17-2218 Cancer Therapy: Preclinical Clinical Cancer Research Synergistic Targeting of the Regulatory and Catalytic Subunits of PI3Kd in Mature B-cell Malignancies Jeffrey D. Cooney1, An-Ping Lin1, Daifeng Jiang1, Long Wang1, Avvaru N. Suhasini1, Jamie Myers1, ZhiJun Qiu1, Albert Wol€ fler2, Heinz Sill2, and Ricardo C.T. Aguiar1,3,4 Abstract Purpose: Aberrant activation of the B-cell receptor (BCR) is loss-of-function were used to map multiple signaling inter- implicated in the pathogenesis of mature B-cell tumors, a mediaries downstream of the BCR. concept validated in part by the clinical success of inhibitors Results: Roflumilast elevates the intracellular levels of of the BCR-related kinases BTK (Bruton's tyrosine kinase) and cyclic-AMP and synergizes with idelalisib in suppressing PI3Kd. These inhibitors have limitations, including the paucity tumor growth and PI3K activity. Mechanistically, we show of complete responses, acquired resistance, and toxicity. Here, that roflumilast suppresses PI3K by inhibiting BCR-mediated we examined the mechanism by which the cyclic-AMP/PDE4 activation of the P85 regulatory subunit, distinguishing itself signaling axis suppresses PI3K, toward identifying a novel from idelalisib, an ATP-competitive inhibitor of the catalytic mechanism-based combinatorial strategy to attack BCR-depen- P110 subunit. Using genetic models, we linked the PDE4- dency in mature B-cell malignancies. regulated modulation of P85 activation to the oncogenic Experimental Design: We used in vitro and in vivo diffuse large kinase SYK. B-cell lymphoma (DLBCL) cell lines and primary chronic Conclusions: These data demonstrate that roflumilast and lymphocytic leukemia (CLL) samples to preclinically evaluate idelalisib suppress PI3K by distinct mechanisms, explaining the effects of the combination of the FDA-approved phospho- the basis for their synergism, and suggest that the repurposing diesterase 4 (PDE4) inhibitor roflumilast and idelalisib on of PDE4 inhibitors to treat BCR-dependent malignancies is cell survival and tumor growth. Genetic models of gain- and warranted. Clin Cancer Res; 24(5); 1103–13. Ó2017 AACR. Introduction Although successful in many instances, the use of ibrutinib (BTK inhibitor) and idelalisib (PI3Kd inhibitor) has not been In mature B lymphocytes, the signals relayed by engagement of devoid of limitations. Ibrutinib displays off-target activity that the B-cell receptor (BCR) stimulate proliferation and are pro- may undermine its therapeutic indexes, it only rarely induces survival. Unsurprisingly, malignant B cells seize on these signals complete remissions, and the emergence of mutant clones raise for their own benefit, at the same time establishing a BCR- concerns about acquired resistance (3). Some of these concerns dependency that exposes a potential vulnerability (1). Exploiting are being addressed with second-generation BTK inhibitors (4). this vulnerability, with BTK and PI3Kd inhibitors, has become an Conversely, further clinical development of idelalisib has been important strategy for the treatment of mature B-cell malignan- limited by toxicity (5, 6). Serious adverse events have been noted cies, perhaps most notably in non-Hodgkin lymphomas (NHLs) when idelalisib is used as a single agent and in particular when in and chronic lymphocytic leukemia (CLL; ref. 2). combination with other biological agents (7, 8). These limitations are of consequence given the essential role of PI3K in transducing 1Division of Hematology and Medical Oncology, Department of Medicine, Uni- the tonic and the pathologic BCR signals, and, hence, the already versity of Texas Health Science Center at San Antonio, San Antonio, Texas. demonstrated potential for its targeted inhibition in the treatment 2Division of Hematology, Medical University of Graz, Graz, Austria. 3Greehey of mature B-cell malignancies. Thus, the identification of alter- Children's Cancer Research Institute, University of Texas Health Sciences Center 4 native approaches to suppress the aberrant PI3K activity, espe- at San Antonio, San Antonio, Texas. South Texas Veterans Health Care System, cially those with a concrete path for clinical development, is an Audie Murphy VA Hospital, San Antonio, San Antonio, Texas. important task. J.D. Cooney and A.-P. Lin contributed equally to this article. The second messenger 3',5'-cyclic adenosine monophosphate Note: Supplementary data for this article are available at Clinical Cancer (cyclic-AMP) delivers inhibitory signals to cells of the innate and Research Online (http://clincancerres.aacrjournals.org/). adaptive immune system (9). In B lymphocytes, the intracellular Corresponding Author: Ricardo Aguiar, Department of Medicine, University of levels of cyclic-AMP are controlled by phosphodiesterase 4 Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, (PDE4; ref. 9). We have recently explored the role of the cyclic- TX 78229. Phone: 210-567-4860; Fax: 210-567-1956; E-mail: AMP/PDE signaling axis in mature B-cell malignancies, in partic- [email protected] ular diffuse large B-cell lymphoma (DLBCL). We correlated high doi: 10.1158/1078-0432.CCR-17-2218 PDE4 expression/activity with poor outcome in DLBCL (10, 11), Ó2017 American Association for Cancer Research. linked the growth suppressive effects of cyclic-AMP in malignant B www.aacrjournals.org 1103 Downloaded from clincancerres.aacrjournals.org on September 27, 2021. © 2018 American Association for Cancer Research. Published OnlineFirst December 15, 2017; DOI: 10.1158/1078-0432.CCR-17-2218 Cooney et al. for only 15 days, except for when this was incompatible with the Translational Relevance experimental design (e.g., generation of CRISPR KO clones by The pharmacologic inhibition of B-cell receptor (BCR) limiting dilution). Primary CLL cells were obtained from 10 adult signaling has changed the treatment of mature B-cell malig- patients diagnosed at the Division of Hematology, Medical Uni- nancies. The clinical success of these agents has been some- versity of Graz, Austria. Biobanking was performed in accordance what tempered by the emergence of clinical resistance, incom- with institutional guidelines, and written informed consent was plete responses, and toxicity. We provide evidence that phos- obtained from each subject. Use of anonymized samples was phodiesterase 4 (PDE4) inhibition also suppresses BCR sig- approved by review boards of the participating Institutions, and nals. We show that combination of the FDA-approved PDE4 the study was performed in accordance to the Declaration of inhibitor roflumilast with the PI3Kd inhibitor idelalisib is Helsinki. Clinical, cytogenetics, and immune phenotypic char- synergistic against diffuse large B-cell lymphoma, in vitro and acteristics of the CLL cases are described in Supplementary Table in vivo. The basis for this synergism is the effect of roflumilast S1. Cell line authenticity was determined by STR profiling and toward the P85 regulatory subunit, in parallel with the inhi- Mycoplasma contamination excluded by a highly sensitive PCR bition of catalytic P110 by idelalisib. These data support the testing, as we reported previously (17). repurposing of roflumilast for the treatment of mature B-cell malignancies in combination with immune-chemotherapy or Reagents and antibodies other biological agents that target the BCR signals. Roflumilast was purchased from Santa Cruz Biotechnology, idelalisib was purchased from MedChem Express or Selleck- chem, and forskolin was from LC Laboratories. Antibodies utilized included: total and phospho-PI3K p85/p55 subunit cells to the inhibition of BCR-related signals (10, 12, 13), and (Tyr458/Tyr199) (#4292 and #4228, respectively), total and demonstrated preclinically and clinically the safety and activity of phospho-BTK (Tyr223) (#56044 and #5082, respectively), total the FDA-approved PDE4 inhibitor roflumilast for the treatment of and phospho-AKT (Thr308) (#9275 and #9272, respectively), mature B-cell tumors (13–15). A common theme of these inves- all from Cell Signaling, PDE4B and SYK (H-56 - sc-25812 and tigations was the consistent suppression of PI3K activity upon 4D10 - sc-1240, respectively, from Santa Cruz Biotechnology), b genetic or pharmacologic depletion of PDE4. These data were also -actin and FLAG (#A-5316 and #F1804, respectively, from of interest because the mechanism by which PDE4 inhibitors Sigma Aldrich). suppress PI3K activity is likely to be distinct from that of ATP- competitor kinase inhibitor Idelalisib, highlighting the potential Genetic models of PDE4B and SYK expression for synergism and clinical applicability of the combination of The generation of SU-DHL6 cells expressing PDE4B wild-type PDE4 and PI3Kd inhibitors. (WT) or PDE4B-phosphodiesterase inactive (PI) mutant was In this report, we show that cyclic-AMP, in a PDE4-depen- reported earlier (10). The PDE4B-PI sequence contains a single dent manner, suppresses PI3Kd lipid kinase activity by inhibit- amino acid substitution (H234S) in the catalytic domain that ing the BCR-mediated phosphorylation of the P85 regulatory abolishes the enzyme's activity. Generation of the SU-DHL6 subunit. Further, using genetic models, we show that the cyclic- cells stably expressing a SYK constitutive-active (CA) mutant has AMP/PDE4 effects on P85 are controlled by SYK. Importantly, also been described (12). This SYK isoform contains three owing in part to their distinct mechanism of action, we dem- amino acid substitutions
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