Pharmacological modulation of CXCR4 cooperates with BET bromodomain inhibition in diffuse large B-cell lymphoma

Clara Recasens-Zorzo, Teresa Cardesa-Salzmann, Paolo Petazzi, Laia Ros-Blanco, Anna Esteve-Arenys, Guillem Clot, Martina Guerrero-Hernández, Vanina Rodríguez, Davide Soldini, Alexandra Valera, Alexandra Moros, Fina Climent, Eva González-Barca, Santiago Mercadal, Leonor Arenillas, Xavier Calvo, José Luís Mate, Gonzalo Gutiérrez-García, Isolda Casanova, Ramón ManguesAlejandra Sanjuan-Pla, Clara Bueno, Pablo Menéndez, Antonio Martínez, Dolors Colomer, Roger Estrada Tejedor, Jordi Teixidó, Elias Campo, Armando López-Guillermo, José Ignacio Borrell, Luis Colomo, Patricia Pérez-Galán, Gaël Roué

Research output: Indexed journal article Articlepeer-review

18 Citations (Scopus)

Abstract

Constitutive activation of the chemokine receptor CXCR4 has been associated with tumor progression, invasion, and chemotherapy resistance in different cancer subtypes. Although the CXCR4 pathway has recently been suggested as an adverse prognostic marker in diffuse large B-cell lymphoma, its biological relevance in this disease remains underexplored. In a homogeneous set of 52 biopsies from patients, an antibody-based cytokine array showed that tissue levels of CXCL12 correlated with high microvessel density and bone marrow involvement at diagnosis, supporting a role for the CXCL12-CXCR4 axis in disease progression. We then identified the tetra-amine IQS-01.01RS as a potent inverse agonist of the receptor, preventing CXCL12-mediated chemotaxis and triggering apoptosis in a panel of 18 cell lines and primary cultures, with superior mobilizing properties in vivo than those of the standard agent. IQS-01.01RS activity was associated with downregulation of p-AKT, p-ERK1/2 and destabilization of MYC, allowing a synergistic interaction with the bromodomain and extra-terminal domain inhibitor, CPI203. In a xenotransplant model of diffuse large B-cell lymphoma, the combination of IQS-01.01RS and CPI203 decreased tumor burden through MYC and p-AKT downregulation, and enhanced the induction of apoptosis. Thus, our results point out an emerging role of CXCL12-CXCR4 in the pathogenesis of diffuse large B-cell lymphoma and support the simultaneous targeting of CXCR4 and bromodomain proteins as a promising, rationale-based strategy for the treatment of this disease.

Original languageEnglish
Pages (from-to)778-788
Number of pages11
JournalHaematologica
Volume104
Issue number4
DOIs
Publication statusPublished - 31 Mar 2019

Fingerprint

Dive into the research topics of 'Pharmacological modulation of CXCR4 cooperates with BET bromodomain inhibition in diffuse large B-cell lymphoma'. Together they form a unique fingerprint.

Cite this