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The dual Syk/JAK inhibitor cerdulatinib antagonizes B-cell receptor and microenvironmental signaling in chronic lymphocytic leukemia

The dual Syk/JAK inhibitor cerdulatinib antagonizes B-cell receptor and microenvironmental signaling in chronic lymphocytic leukemia
The dual Syk/JAK inhibitor cerdulatinib antagonizes B-cell receptor and microenvironmental signaling in chronic lymphocytic leukemia
Purpose: B-cell receptor (BCR)-associated kinase inhibitors such as ibrutinib have revolutionised the treatment of chronic lymphocytic leukemia (CLL). However, these agents are not curative and resistance is already emerging in a proportion of patients. Interleukin-4 (IL-4), expressed in CLL lymph nodes, can augment BCR-signalling and reduce the effectiveness of BCR-kinase inhibitors. Therefore simultaneous targeting of the IL-4- and BCR-signalling pathways by cerdulatinib, a novel dual Syk/JAK inhibitor currently in clinical trials (NCT01994382), may improve treatment responses in patients.

Experimental Design: PBMCs from CLL patients were treated with cerdulatinib alone or in combination with venetoclax. Cell death, chemokine and cell signalling assay were performed and analysed by flow cytometry, immunoblotting, Q-PCR and ELISA as indicated.

Results: at concentrations achievable in patients, cerdulatinib inhibited BCR- and IL-4-induced downstream signalling in CLL cells using multiple read outs and prevented anti-IgM- and nurse-like cell (NLC)-mediated CCL3/CCL4 production. Cerdulatinib induced apoptosis of CLL cells, in a time- and concentration dependent manner, and particularly in IGHV unmutated samples with greater BCR-signalling capacity and response to IL-4, or samples expressing higher levels of sIgM, CD49d+ or ZAP70+. Cerdulatinib overcame anti-IgM, IL-4/CD40L or NLC-mediated protection by preventing upregulation of MCL-1- and BCL-XL, however BCL-2 expression was unaffected. Furthermore in samples treated with IL-4/CD40L, cerdulatinib synergised with venetoclax in vitro to induce greater apoptosis than either drug alone.

Conclusion: cerdulatinib is a promising therapeutic for the treatment of CLL either alone or in combination with venetoclax, with the potential to target critical survival pathways in this currently incurable disease
Journal Article
1078-0432
2313-2324
Blunt, Matthew D.
b1109de3-6045-4bc3-bd77-6cf26504697d
Koehrer, Stefan
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Dobson, Rachel C.
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Larrayoz, Marta
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Wilmore, Sarah
b3ae1360-0c10-440b-87d1-e9be4d1c326e
Hayman, Alice
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Parnell, Jack
67935965-6a59-4166-8b5c-2e96e2a1c9b4
Smith, Lindsay D.
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Davies, Andrew
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Johnson, Peter W.M.
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Conley, Pamela B.
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Pandey, Anjali
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Strefford, Jonathan C.
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Stevenson, Freda K.
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Packham, Graham
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Forconi, Francesco
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Coffey, Greg P
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Burger, Jan A.
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Steele, Andrew J.
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Blunt, Matthew D.
b1109de3-6045-4bc3-bd77-6cf26504697d
Koehrer, Stefan
debe39c4-41c7-44c0-a3a5-9489423890f4
Dobson, Rachel C.
c2ef3195-3497-4d01-b75e-e0f2dd668ec3
Larrayoz, Marta
952a54b7-c539-4f37-8818-0129e634e999
Wilmore, Sarah
b3ae1360-0c10-440b-87d1-e9be4d1c326e
Hayman, Alice
86cd64bc-514f-43d6-bf44-40e07f7899f4
Parnell, Jack
67935965-6a59-4166-8b5c-2e96e2a1c9b4
Smith, Lindsay D.
1d44c2d0-d5af-411e-b6cd-9b5633f2eb1e
Davies, Andrew
0fe6a40a-10d1-4ade-a7e6-d1dceb2470af
Johnson, Peter W.M.
3f6068ce-171e-4c2c-aca9-dc9b6a37413f
Conley, Pamela B.
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Pandey, Anjali
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Strefford, Jonathan C.
3782b392-f080-42bf-bdca-8aa5d6ca532f
Stevenson, Freda K.
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Packham, Graham
fdabe56f-2c58-469c-aadf-38878f233394
Forconi, Francesco
ce9ed873-58cf-4876-bf3a-9ba1d163edc8
Coffey, Greg P
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Burger, Jan A.
ecbcaaa4-888a-40f5-9d17-009cef969f0d
Steele, Andrew J.
4349f6aa-2e3a-49a8-be73-7716056ae089

Blunt, Matthew D., Koehrer, Stefan, Dobson, Rachel C., Larrayoz, Marta, Wilmore, Sarah, Hayman, Alice, Parnell, Jack, Smith, Lindsay D., Davies, Andrew, Johnson, Peter W.M., Conley, Pamela B., Pandey, Anjali, Strefford, Jonathan C., Stevenson, Freda K., Packham, Graham, Forconi, Francesco, Coffey, Greg P, Burger, Jan A. and Steele, Andrew J. (2017) The dual Syk/JAK inhibitor cerdulatinib antagonizes B-cell receptor and microenvironmental signaling in chronic lymphocytic leukemia. Clinical Cancer Research, 23 (9), 2313-2324. (doi:10.1158/1078-0432.CCR-16-1662).

Record type: Article

Abstract

Purpose: B-cell receptor (BCR)-associated kinase inhibitors such as ibrutinib have revolutionised the treatment of chronic lymphocytic leukemia (CLL). However, these agents are not curative and resistance is already emerging in a proportion of patients. Interleukin-4 (IL-4), expressed in CLL lymph nodes, can augment BCR-signalling and reduce the effectiveness of BCR-kinase inhibitors. Therefore simultaneous targeting of the IL-4- and BCR-signalling pathways by cerdulatinib, a novel dual Syk/JAK inhibitor currently in clinical trials (NCT01994382), may improve treatment responses in patients.

Experimental Design: PBMCs from CLL patients were treated with cerdulatinib alone or in combination with venetoclax. Cell death, chemokine and cell signalling assay were performed and analysed by flow cytometry, immunoblotting, Q-PCR and ELISA as indicated.

Results: at concentrations achievable in patients, cerdulatinib inhibited BCR- and IL-4-induced downstream signalling in CLL cells using multiple read outs and prevented anti-IgM- and nurse-like cell (NLC)-mediated CCL3/CCL4 production. Cerdulatinib induced apoptosis of CLL cells, in a time- and concentration dependent manner, and particularly in IGHV unmutated samples with greater BCR-signalling capacity and response to IL-4, or samples expressing higher levels of sIgM, CD49d+ or ZAP70+. Cerdulatinib overcame anti-IgM, IL-4/CD40L or NLC-mediated protection by preventing upregulation of MCL-1- and BCL-XL, however BCL-2 expression was unaffected. Furthermore in samples treated with IL-4/CD40L, cerdulatinib synergised with venetoclax in vitro to induce greater apoptosis than either drug alone.

Conclusion: cerdulatinib is a promising therapeutic for the treatment of CLL either alone or in combination with venetoclax, with the potential to target critical survival pathways in this currently incurable disease

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Cerdulatinib paper CCR eprints edition.pdf - Accepted Manuscript
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Accepted/In Press date: 10 September 2016
e-pub ahead of print date: 3 October 2016
Published date: 1 May 2017
Additional Information: ©2016 American Association for Cancer Research.
Keywords: Journal Article
Organisations: Cancer Sciences

Identifiers

Local EPrints ID: 401087
URI: http://eprints.soton.ac.uk/id/eprint/401087
ISSN: 1078-0432
PURE UUID: 4637b1a1-727a-4185-95f6-1d1277c94940
ORCID for Sarah Wilmore: ORCID iD orcid.org/0000-0002-6929-0267
ORCID for Peter W.M. Johnson: ORCID iD orcid.org/0000-0003-2306-4974
ORCID for Jonathan C. Strefford: ORCID iD orcid.org/0000-0002-0972-2881
ORCID for Freda K. Stevenson: ORCID iD orcid.org/0000-0002-0933-5021
ORCID for Graham Packham: ORCID iD orcid.org/0000-0002-9232-5691
ORCID for Andrew J. Steele: ORCID iD orcid.org/0000-0003-0667-1596

Catalogue record

Date deposited: 07 Oct 2016 08:54
Last modified: 17 Dec 2019 06:36

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Contributors

Author: Stefan Koehrer
Author: Rachel C. Dobson
Author: Marta Larrayoz
Author: Sarah Wilmore ORCID iD
Author: Alice Hayman
Author: Jack Parnell
Author: Lindsay D. Smith
Author: Andrew Davies
Author: Pamela B. Conley
Author: Anjali Pandey
Author: Graham Packham ORCID iD
Author: Greg P Coffey
Author: Jan A. Burger

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