Pharmacological modulation of CXCR4 cooperates with BET bromodomain inhibition in diffuse large B-cell lymphoma
Por:
Recasens-Zorzo, C, Cardesa-Salzmann, T, Petazzi, P, Ros-Blanco, L, Esteve-Arenys, A, Clot, G, Guerrero-Hernandez, M, Rodriguez, V, Soldini, D, Valera, A, Moros, A, Climent, F, Gonzalez-Barca, E, Mercadal, S, Arenillas, L, Calvo, X, Mate, JL, Gutierrez-Garcia, G, Casanova, I, Mangues, R, Sanjuan-Pla, A, Bueno, C, Menendez, P, Martinez, A, Colomer, D, Tejedor, RE, Teixido, J, Campo, E, Lopez-Guillermo, A, Borrell, JI, Colomo, L, Perez-Galan, P, Roui, G
Publicada:
31 mar 2019
Resumen:
Constitutive activation of the chemokine receptor CXCR4 has be en 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.
Filiaciones:
Recasens-Zorzo, C:
CIBERONC, Inst Invest Biomed August Pi & Sunyer IDIBAPS, Div Hematooncol, Barcelona, Spain
Cardesa-Salzmann, T:
Hosp Clin Barcelona, Dept Pathol, Hematopathol Unit, Barcelona, Spain
Petazzi, P:
Univ Barcelona, Josep Carreras Leukemia Res Inst, Sch Med, Dept Biomed, Barcelona, Spain
Ros-Blanco, L:
Univ Ramon Llull, IQS Sch Engn, Grup Engn Mol, Barcelona, Spain
Esteve-Arenys, A:
CIBERONC, Inst Invest Biomed August Pi & Sunyer IDIBAPS, Div Hematooncol, Barcelona, Spain
Clot, G:
CIBERONC, Inst Invest Biomed August Pi & Sunyer IDIBAPS, Div Hematooncol, Barcelona, Spain
Guerrero-Hernandez, M:
CIBERONC, Inst Invest Biomed August Pi & Sunyer IDIBAPS, Div Hematooncol, Barcelona, Spain
Rodriguez, V:
CIBERONC, Inst Invest Biomed August Pi & Sunyer IDIBAPS, Div Hematooncol, Barcelona, Spain
Soldini, D:
Hosp Clin Barcelona, Dept Pathol, Hematopathol Unit, Barcelona, Spain
Valera, A:
Hosp Clin Barcelona, Dept Pathol, Hematopathol Unit, Barcelona, Spain
Moros, A:
CIBERONC, Inst Invest Biomed August Pi & Sunyer IDIBAPS, Div Hematooncol, Barcelona, Spain
Climent, F:
Hosp Univ Bellvitge, Pathol Dept, Lhospitalet De Llobregat, Spain
Gonzalez-Barca, E:
Hosp Duran & Reynals, Inst Catala Oncol, Lhospitalet De Llobregat, Spain
Mercadal, S:
Hosp Duran & Reynals, Inst Catala Oncol, Lhospitalet De Llobregat, Spain
Arenillas, L:
Hosp del Mar, IMIM, Pathol Dept, Barcelona, Spain
Calvo, X:
Hosp del Mar, IMIM, Pathol Dept, Barcelona, Spain
Mate, JL:
Hosp Badalona Germans Trias & Pujol, Pathol Dept, Badalona, Spain
Gutierrez-Garcia, G:
Hosp Clin Barcelona, Dept Hematol, Barcelona, Spain
Casanova, I:
Univ Barcelona, Josep Carreras Leukemia Res Inst, Sch Med, Dept Biomed, Barcelona, Spain
IIB St Pau, Grp Oncogenesi & Antitumorals, Barcelona, Spain
BBN, CIBER, Barcelona, Spain
Mangues, R:
Univ Barcelona, Josep Carreras Leukemia Res Inst, Sch Med, Dept Biomed, Barcelona, Spain
IIB St Pau, Grp Oncogenesi & Antitumorals, Barcelona, Spain
BBN, CIBER, Barcelona, Spain
Sanjuan-Pla, A:
Hlth Res Inst La Fe, Hematol Res Grp, Valencia, Spain
Bueno, C:
Univ Barcelona, Josep Carreras Leukemia Res Inst, Sch Med, Dept Biomed, Barcelona, Spain
Menendez, P:
Univ Barcelona, Josep Carreras Leukemia Res Inst, Sch Med, Dept Biomed, Barcelona, Spain
CIBERONC, ICREA, Barcelona, Spain
Martinez, A:
CIBERONC, Inst Invest Biomed August Pi & Sunyer IDIBAPS, Div Hematooncol, Barcelona, Spain
Hosp Clin Barcelona, Dept Pathol, Hematopathol Unit, Barcelona, Spain
Colomer, D:
CIBERONC, Inst Invest Biomed August Pi & Sunyer IDIBAPS, Div Hematooncol, Barcelona, Spain
Hosp Clin Barcelona, Dept Pathol, Hematopathol Unit, Barcelona, Spain
Tejedor, RE:
Univ Ramon Llull, IQS Sch Engn, Grup Engn Mol, Barcelona, Spain
Teixido, J:
Univ Ramon Llull, IQS Sch Engn, Grup Engn Mol, Barcelona, Spain
Campo, E:
CIBERONC, Inst Invest Biomed August Pi & Sunyer IDIBAPS, Div Hematooncol, Barcelona, Spain
Hosp Clin Barcelona, Dept Pathol, Hematopathol Unit, Barcelona, Spain
Lopez-Guillermo, A:
CIBERONC, Inst Invest Biomed August Pi & Sunyer IDIBAPS, Div Hematooncol, Barcelona, Spain
Hosp Clin Barcelona, Dept Hematol, Barcelona, Spain
Borrell, JI:
Univ Ramon Llull, IQS Sch Engn, Grup Engn Mol, Barcelona, Spain
Colomo, L:
Hosp Clin Barcelona, Dept Pathol, Hematopathol Unit, Barcelona, Spain
Hosp del Mar, IMIM, Pathol Dept, Barcelona, Spain
Perez-Galan, P:
CIBERONC, Inst Invest Biomed August Pi & Sunyer IDIBAPS, Div Hematooncol, Barcelona, Spain
Roui, G:
CIBERONC, Inst Invest Biomed August Pi & Sunyer IDIBAPS, Div Hematooncol, Barcelona, Spain
Vall dHebron Univ Hosp, Vall dHebron Inst Oncol, Dept Hematol, Lab Expt Hematol, Barcelona, Spain
Gold, Green Published
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