Synergistic targeting of the regulatory and catalytic subunits of pi3kd in mature b-cell malignancies

Jeffrey D. Cooney, An Ping Lin, Daifeng Jiang, Long Wang, Avvaru N. Suhasini, Jamie Myers, Zhi Jun Qiu, Albert Wolfler, Heinz Sill, Ricardo C.T. Aguiar

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Purpose: Aberrant activation of the B-cell receptor (BCR) is implicated in the pathogenesis of mature B-cell tumors, a concept validated in part by the clinical success of inhibitors of the BCR-related kinases BTK (Bruton's tyrosine kinase) and PI3Kd. These inhibitors have limitations, including the paucity of complete responses, acquired resistance, and toxicity. Here, we examined the mechanism by which the cyclic-AMP/PDE4 signaling axis suppresses PI3K, toward identifying a novel mechanism-based combinatorial strategy to attack BCR-dependency in mature B-cell malignancies. Experimental Design: We used in vitro and in vivo diffuse large B-cell lymphoma (DLBCL) cell lines and primary chronic lymphocytic leukemia (CLL) samples to preclinically evaluate the effects of the combination of the FDA-approved phosphodiesterase 4 (PDE4) inhibitor roflumilast and idelalisib on cell survival and tumor growth. Genetic models of gain- and loss-of-function were used to map multiple signaling intermediaries downstream of the BCR. Results: Roflumilast elevates the intracellular levels of cyclic-AMP and synergizes with idelalisib in suppressing tumor growth and PI3K activity. Mechanistically, we show that roflumilast suppresses PI3K by inhibiting BCR-mediated activation of the P85 regulatory subunit, distinguishing itself from idelalisib, an ATP-competitive inhibitor of the catalytic P110 subunit. Using genetic models, we linked the PDE4-regulated modulation of P85 activation to the oncogenic kinase SYK. Conclusions: These data demonstrate that roflumilast and idelalisib suppress PI3K by distinct mechanisms, explaining the basis for their synergism, and suggest that the repurposing of PDE4 inhibitors to treat BCR-dependent malignancies is warranted.

Original languageEnglish (US)
Pages (from-to)1103-1113
Number of pages11
JournalClinical Cancer Research
Volume24
Issue number5
DOIs
StatePublished - Mar 1 2018

Fingerprint

Catalytic Domain
B-Lymphocytes
Phosphatidylinositol 3-Kinases
Neoplasms
Type 4 Cyclic Nucleotide Phosphodiesterase
Phosphodiesterase 4 Inhibitors
Genetic Models
Cyclic AMP
Phosphotransferases
Lymphoma, Large B-Cell, Diffuse
B-Cell Chronic Lymphocytic Leukemia
Growth
Cell Survival
Research Design
Adenosine Triphosphate
Cell Line
Roflumilast
idelalisib

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Synergistic targeting of the regulatory and catalytic subunits of pi3kd in mature b-cell malignancies. / Cooney, Jeffrey D.; Lin, An Ping; Jiang, Daifeng; Wang, Long; Suhasini, Avvaru N.; Myers, Jamie; Qiu, Zhi Jun; Wolfler, Albert; Sill, Heinz; Aguiar, Ricardo C.T.

In: Clinical Cancer Research, Vol. 24, No. 5, 01.03.2018, p. 1103-1113.

Research output: Contribution to journalArticle

Cooney, JD, Lin, AP, Jiang, D, Wang, L, Suhasini, AN, Myers, J, Qiu, ZJ, Wolfler, A, Sill, H & Aguiar, RCT 2018, 'Synergistic targeting of the regulatory and catalytic subunits of pi3kd in mature b-cell malignancies', Clinical Cancer Research, vol. 24, no. 5, pp. 1103-1113. https://doi.org/10.1158/1078-0432.CCR-17-2218
Cooney, Jeffrey D. ; Lin, An Ping ; Jiang, Daifeng ; Wang, Long ; Suhasini, Avvaru N. ; Myers, Jamie ; Qiu, Zhi Jun ; Wolfler, Albert ; Sill, Heinz ; Aguiar, Ricardo C.T. / Synergistic targeting of the regulatory and catalytic subunits of pi3kd in mature b-cell malignancies. In: Clinical Cancer Research. 2018 ; Vol. 24, No. 5. pp. 1103-1113.
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AU - Cooney, Jeffrey D.

AU - Lin, An Ping

AU - Jiang, Daifeng

AU - Wang, Long

AU - Suhasini, Avvaru N.

AU - Myers, Jamie

AU - Qiu, Zhi Jun

AU - Wolfler, Albert

AU - Sill, Heinz

AU - Aguiar, Ricardo C.T.

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N2 - Purpose: Aberrant activation of the B-cell receptor (BCR) is implicated in the pathogenesis of mature B-cell tumors, a concept validated in part by the clinical success of inhibitors of the BCR-related kinases BTK (Bruton's tyrosine kinase) and PI3Kd. These inhibitors have limitations, including the paucity of complete responses, acquired resistance, and toxicity. Here, we examined the mechanism by which the cyclic-AMP/PDE4 signaling axis suppresses PI3K, toward identifying a novel mechanism-based combinatorial strategy to attack BCR-dependency in mature B-cell malignancies. Experimental Design: We used in vitro and in vivo diffuse large B-cell lymphoma (DLBCL) cell lines and primary chronic lymphocytic leukemia (CLL) samples to preclinically evaluate the effects of the combination of the FDA-approved phosphodiesterase 4 (PDE4) inhibitor roflumilast and idelalisib on cell survival and tumor growth. Genetic models of gain- and loss-of-function were used to map multiple signaling intermediaries downstream of the BCR. Results: Roflumilast elevates the intracellular levels of cyclic-AMP and synergizes with idelalisib in suppressing tumor growth and PI3K activity. Mechanistically, we show that roflumilast suppresses PI3K by inhibiting BCR-mediated activation of the P85 regulatory subunit, distinguishing itself from idelalisib, an ATP-competitive inhibitor of the catalytic P110 subunit. Using genetic models, we linked the PDE4-regulated modulation of P85 activation to the oncogenic kinase SYK. Conclusions: These data demonstrate that roflumilast and idelalisib suppress PI3K by distinct mechanisms, explaining the basis for their synergism, and suggest that the repurposing of PDE4 inhibitors to treat BCR-dependent malignancies is warranted.

AB - Purpose: Aberrant activation of the B-cell receptor (BCR) is implicated in the pathogenesis of mature B-cell tumors, a concept validated in part by the clinical success of inhibitors of the BCR-related kinases BTK (Bruton's tyrosine kinase) and PI3Kd. These inhibitors have limitations, including the paucity of complete responses, acquired resistance, and toxicity. Here, we examined the mechanism by which the cyclic-AMP/PDE4 signaling axis suppresses PI3K, toward identifying a novel mechanism-based combinatorial strategy to attack BCR-dependency in mature B-cell malignancies. Experimental Design: We used in vitro and in vivo diffuse large B-cell lymphoma (DLBCL) cell lines and primary chronic lymphocytic leukemia (CLL) samples to preclinically evaluate the effects of the combination of the FDA-approved phosphodiesterase 4 (PDE4) inhibitor roflumilast and idelalisib on cell survival and tumor growth. Genetic models of gain- and loss-of-function were used to map multiple signaling intermediaries downstream of the BCR. Results: Roflumilast elevates the intracellular levels of cyclic-AMP and synergizes with idelalisib in suppressing tumor growth and PI3K activity. Mechanistically, we show that roflumilast suppresses PI3K by inhibiting BCR-mediated activation of the P85 regulatory subunit, distinguishing itself from idelalisib, an ATP-competitive inhibitor of the catalytic P110 subunit. Using genetic models, we linked the PDE4-regulated modulation of P85 activation to the oncogenic kinase SYK. Conclusions: These data demonstrate that roflumilast and idelalisib suppress PI3K by distinct mechanisms, explaining the basis for their synergism, and suggest that the repurposing of PDE4 inhibitors to treat BCR-dependent malignancies is warranted.

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