TY - JOUR
T1 - Halting the FGF/FGFR axis leads to antitumor activity in Waldenström macroglobulinemia by silencing MYD88
AU - Sacco, Antonio
AU - Federico, Cinzia
AU - Giacomini, Arianna
AU - Caprio, Cinzia
AU - Maccarinelli, Federica
AU - Todoerti, Katia
AU - Favasuli, Vanessa
AU - Anastasia, Antonella
AU - Motta, Marina
AU - Russo, Domenico
AU - Rossi, Giuseppe
AU - Bozza, Nicole
AU - Castelli, Riccardo
AU - Neri, Antonino
AU - Ronca, Roberto
AU - Cattaneo, Chiara
AU - Tucci, Alessandra
AU - Mor, Marco
AU - Presta, Marco
AU - Roccaro, Aldo M.
N1 - Funding Information:
Conflict-of-interest disclosure: A.M.R. has received research funding from AstraZeneca, European Hematology Association, Transcan2-ERANET, and Italian Association for Cancer Research (Fondazione AIRC) and has received honoraria from Amgen, Celgene, and Janssen. G.R. has received consultancy fees from Daiichi-Sankyo; served on advisory boards for Roche, Janssen, Celgene, Amgen, Gilead, Sanofi, Abbvie, Pfizer, Jazz, and Astellas; and has received honoraria for lectures for Novartis, Mundipharma, BMS, and Sandoz. The remaining authors declare no competing financial interests.
Funding Information:
This work is supported by Fondazione AIRC, Fondazione Regionale per la Ricerca (A.M.R.), Biomedica, ERA-NET TRANSCAN-2: Associazione Italiana Contro le Leucemie-linfomi e Mieloma (AIL) Brescia, AIRC IG 16722, Italian Ministry of Health (Ricerca Corrente 2019) (A.N.), Fondazione Cariplo grant 2016-0570 (A.G.), Associazione Italiana Ricerca sul Cancro (AIRC IG 2019-ID.23151) (R.R.), and a fellowship by Fondazione Veronesi (F.M.).
Publisher Copyright:
© 2021 American Society of Hematology
PY - 2021/5/6
Y1 - 2021/5/6
N2 - The human fibroblast growth factor/fibroblast growth factor receptor (FGF/FGFR) axis deregulation is largely involved in supporting the pathogenesis of hematologic malignancies, including Waldenström macroglobulinemia (WM). WM is still an incurable disease, and patients succumb because of disease progression. Therefore, novel therapeutics designed to specifically target deregulated signaling pathways in WM are required. We aimed to investigate the role of FGF/FGFR system blockade in WM by using a pan-FGF trap molecule (NSC12). Wide-transcriptome profiling confirmed inhibition of FGFR signaling in NSC12-treated WM cells; unveiling a significant inhibition of MYD88 was also confirmed at the protein level. Importantly, the NSC12-dependent silencing of MYD88 was functionally active, as it led to inhibition of MYD88-driven pathways, such as BTK and SYK, as well as the MYD88-downstream target HCK. Of note, both canonical and noncanonical NF-κB cascades were downregulated in WM cells upon NSC12 treatment. Functional sequelae exerted by NSC12 in WM cells were studied, demonstrating significant inhibition of WM cell growth, induction of WM cell apoptosis, halting MAPK, JAK/STAT3, and PI3K-Akt pathways. Importantly, NSC12 exerted an anti-WM effect even in the presence of bone marrow microenvironment, both in vitro and in vivo. Our studies provide the evidence for using NSC12 as a specific FGF/FGFR system inhibitor, thus representing a novel therapeutic strategy in WM.
AB - The human fibroblast growth factor/fibroblast growth factor receptor (FGF/FGFR) axis deregulation is largely involved in supporting the pathogenesis of hematologic malignancies, including Waldenström macroglobulinemia (WM). WM is still an incurable disease, and patients succumb because of disease progression. Therefore, novel therapeutics designed to specifically target deregulated signaling pathways in WM are required. We aimed to investigate the role of FGF/FGFR system blockade in WM by using a pan-FGF trap molecule (NSC12). Wide-transcriptome profiling confirmed inhibition of FGFR signaling in NSC12-treated WM cells; unveiling a significant inhibition of MYD88 was also confirmed at the protein level. Importantly, the NSC12-dependent silencing of MYD88 was functionally active, as it led to inhibition of MYD88-driven pathways, such as BTK and SYK, as well as the MYD88-downstream target HCK. Of note, both canonical and noncanonical NF-κB cascades were downregulated in WM cells upon NSC12 treatment. Functional sequelae exerted by NSC12 in WM cells were studied, demonstrating significant inhibition of WM cell growth, induction of WM cell apoptosis, halting MAPK, JAK/STAT3, and PI3K-Akt pathways. Importantly, NSC12 exerted an anti-WM effect even in the presence of bone marrow microenvironment, both in vitro and in vivo. Our studies provide the evidence for using NSC12 as a specific FGF/FGFR system inhibitor, thus representing a novel therapeutic strategy in WM.
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UR - http://www.scopus.com/inward/citedby.url?scp=85105281128&partnerID=8YFLogxK
U2 - 10.1182/blood.2020008414
DO - 10.1182/blood.2020008414
M3 - Article
C2 - 33197938
AN - SCOPUS:85105281128
VL - 137
SP - 2495
EP - 2508
JO - Blood
JF - Blood
SN - 0006-4971
IS - 18
ER -