Page 42 - 2021_04-Haematologica-web

Ferrata Storti Foundation
Haematologica 2021 Volume 106(4):958-967
Hematologic cancers
Novel pyrrolobenzodiazepine benzofused hybrid molecules inhibit nuclear factor-κB activity and synergize with bortezomib and ibrutinib
in hematologic cancers
Thomas Lewis,1 David B. Corcoran,2 David E. Thurston,2 Peter J. Giles,1,3 Kevin Ashelford,1,3 Elisabeth J. Walsby,1 Christopher D. Fegan,1 Andrea G. S. Pepper,4 Khondaker Miraz Rahman2# and Chris Pepper1,4#
1Division of Cancer & Genetics, Cardiff University School of Medicine, Cardiff; 2School of Cancer and Pharmaceutical Science, King’s College London, Franklin-Wilkins Building, London; 3Wales Gene Park, Heath Park, Cardiff and 4Brighton and Sussex Medical School, University of Sussex, Brighton, UK
#KMR and CP contributed equally as co-senior authors.
inhibition of NF-κB with low nanomolar LD 50
ABSTRACT
Chronic lymphocytic leukemia (CLL) and multiple myeloma are incurable hematologic malignancies that are pathologically linked with aberrant nuclear factor-kappa B (NF-κB) activation. In this study, we identified a group of novel C8-linked benzofused pyrrolo[2,1- c][1,4]benzodiazepine monomeric hybrids capable of sequence-selective
values in CLL (n=46) and multiple myeloma cell lines (n=5). The lead compound, DC-1-192, signif- icantly inhibited NF-κB DNA binding after just 4 h of exposure, demon- strating inhibitory effects on both canonical and non-canonical NF-κB subunits. In primary CLL cells, sensitivity to DC-1-192 was inversely cor- related with RelA subunit expression (r2=0.2) and samples with BIRC3 or NOTCH1 mutations showed increased sensitivity (P=0.001). RNA- sequencing and gene set enrichment analysis confirmed the over-repre- sentation of NF-κB regulated genes in the downregulated gene list. Furthermore, in vivo efficacy studies in NOD/SCID mice, using a systemic RPMI 8226 human multiple myeloma xenograft model, showed that DC- 1-192 significantly prolonged survival (P=0.017). In addition, DC1-192 showed synergy with bortezomib and ibrutinib; synergy with ibrutinib was enhanced when CLL cells were co-cultured on CD40L-expressing fibroblasts in order to mimic the cytoprotective lymph node microenvi- ronment (P=0.01). Given that NF-κB plays a role in both bortezomib and ibrutinib resistance mechanisms, these data provide a strong rationale for the use of DC-1-192 in the treatment of NF-κB-driven cancers, particular-
ly in the context of relapsed/refractory disease.
Introduction
Nuclear factor kappa B (NF-κB) denotes a family of homo- and heterodimeric transcription factors composed of five subunits: p65 (RelA), p50, RelB, p52 and c- Rel.1 These subunits exert their effects via the canonical or non-canonical signaling pathways.2 NF-κB is maintained in an inactive state in the cytoplasm but following IκB kinase (IKK) activation NF-κB is shuttled into the nucleus where it exerts its transcriptional effects.3 NF-κB regulates the transcription of genes that are essential for cell survival, proliferation, inflammation and invasion/metastasis. These processes are commonly dysregulated in cancers, including CLL and multiple myeloma, leading to the constitutive aberrant activation of NF-κB.2-4 Indeed, NF- κB has been shown to play a central role in disease progression and drug resistance in these hematologic cancers.5,6 While treatment with currently established thera- pies, such as the proteasome inhibitor bortezomib or the BTK inhibitor ibrutinib,
Correspondence:
CHRIS PEPPER
c.pepper@bsms.ac.uk
Received: September 17, 2019. Accepted: March 24, 2020. Pre-published: May 7, 2020.
https://doi.org/10.3324/haematol.2019.238584
©2021 Ferrata Storti Foundation
Material published in Haematologica is covered by copyright. All rights are reserved to the Ferrata Storti Foundation. Use of published material is allowed under the following terms and conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode. Copies of published material are allowed for personal or inter- nal use. Sharing published material for non-commercial pur- poses is subject to the following conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode, sect. 3. Reproducing and sharing published material for com- mercial purposes is not allowed without permission in writing from the publisher.
958
haematologica | 2021; 106(4)
ARTICLE