Co-targeting aurora kinase with PD-L1 and PI3K abrogates immune checkpoint mediated proliferation in peripheral T-cell lymphoma: a novel therapeutic strategy
Author
Islam, SharifulVick, Eric
Huber, Bryan
Morales, Carla
Spier, Catherine
Cooke, Laurence
Weterings, Eric
Mahadevan, Daruka
Affiliation
Univ Arizona, Ctr Canc, Canc Biol GIDPUniv Arizona, Dept Hematopathol
Univ Arizona, Ctr Canc, Dept Med
Univ Arizona, Dept Radiat Oncol
Issue Date
2017-11-01
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IMPACT JOURNALS LLCCitation
Co-targeting aurora kinase with PD-L1 and PI3K abrogates immune checkpoint mediated proliferation in peripheral T-cell lymphoma: a novel therapeutic strategy 2017, 8 (59) OncotargetJournal
OncotargetRights
© Islam et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0).Collection Information
This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.edu.Abstract
Peripheral T-cell non-Hodgkin lymphoma (PTCL) are heterogeneous, rare, and aggressive diseases mostly incurable with current cell cycle therapies. Aurora kinases (AKs) are key regulators of mitosis that drive PTCL proliferation. Alisertib (AK inhibitor) has a response rate similar to 30% in relapsed and refractory PTCL (SWOG1108). Since PTCL are derived from CD4(+)/CD8(+) cells, we hypothesized that Program Death Ligand-1 (PDL1) expression is essential for uncontrolled proliferation. Combination of alisertib with PI3K alpha (MLN1117) or pan-PI3K inhibition (PF-04691502) or vincristine (VCR) was highly synergistic in PTCL cells. Expression of PD-L1 relative to PD-1 is high in PTCL biopsies (similar to 9-fold higher) and cell lines. Combination of alisertib with pan-PI3K inhibition or VCR significantly reduced PD-L1, NF-kappa B expression and inhibited phosphorylation of AKT, ERK1/2 and AK with enhanced apoptosis. In a SCID PTCL xenograft mouse model, alisertib displayed high synergism with MLN1117. In a syngeneic PTCL mouse xenograft model alisertib demonstrated tumor growth inhibition (TGI) similar to 30%, whilst anti-PD-L1 therapy alone was ineffective. Alisertib + anti-PD-L1 resulted in TGI > 90% indicative of a synthetic lethal interaction. PF-04691502 + alisertib + anti-PD-L1 + VCR resulted in TGI 100%. Overall, mice tolerated the treatments well. Co-targeting AK, PI3K and PD-L1 is a rational and novel therapeutic strategy for PTCL.ISSN
1949-2553PubMed ID
29245981Version
Final published versionSponsors
The Hope Foundation Impact Award (SWOG); Lymphoma SPORE; West Cancer Center/UTHSC; WCC/UTHSCAdditional Links
http://www.oncotarget.com/fulltext/22222ae974a485f413a2113503eed53cd6c53
10.18632/oncotarget.22222
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Except where otherwise noted, this item's license is described as © Islam et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0).