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Halting the FGF/FGFR axis leads to anti-tumor activity in Waldenström’s Macroglobulinemia by silencing MYD88

ABSTRACT: Halting the FGF/FGFR axis leads to anti-tumor activity in Waldenström’s Macroglobulinemia by silencing MYD88

PROVIDER: PRJNA648870 | ENA |

REPOSITORIES: ENA

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Halting the FGF/FGFR axis leads to anti-tumor activity in Waldenström’s Macroglobulinemia by silencing MYD88

Project description: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’s Macroglobulinemia (WM). WM is still an incurable disease, and patients succumb due to 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 blocking system 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 also confirmed at 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 non-canonical NFB cascades were down-regulated 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.

2021-08-27 | GSE155155 | GEO

Single cell analysis of MYD88 L265P and MYD88 WT Waldenström macroglobulinemia (WM) patients

Project description:Single cell analysis of MYD88 L265P and MYD88 WT Waldenström macroglobulinemia (WM) patients

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Acquired FGFR and FGF alterations confer resistance to estrogen receptor (ER) targeted therapy in ER+ metastatic breast cancer

Project description:Beyond acquired mutations in the estrogen receptor (ER), mechanisms of resistance to ER-directed therapies in ER+ breast cancer have not been clearly defined. We conducted a genome-scale functional screen spanning 10,135 genes to investigate genes whose overexpression confer resistance to selective estrogen receptor degraders. Pathway analysis of candidate resistance genes demonstrated that the FGFR, ERBB, insulin receptor, and MAPK pathways represented key modalities of resistance. In parallel, we performed whole exome sequencing in paired pre-treatment and post-resistance biopsies from 60 patients with ER+ metastatic breast cancer who had developed resistance to ER-targeted therapy. The FGFR pathway was altered via FGFR1, FGFR2, or FGF3/FGF4 amplifications or FGFR2 mutations in 24 (40%) of the post-resistance biopsies. In 12 of the 24 post-resistance tumors exhibiting FGFR/FGF alterations, these alterations were not detected in the corresponding pre-treatment tumors, suggesting that they were acquired or enriched under the selective pressure of ER-directed therapy. In vitro experiments in ER+ breast cancer cells confirmed that FGFR/FGF alterations led to fulvestrant resistance as well as cross-resistance to the CDK4/6 inhibitor palbociclib, through activation of the MAPK pathway. The resistance phenotypes were reversed by FGFR inhibitors and, to a lesser extent, MEK inhibitors, suggesting potential treatment strategies.

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Single cell analysis of MYD88 L265P and MYD88 WT Waldenström macroglobulinemia (WM) patients

Project description:To elucidate the differences occurring in the B cell composition between WM patients, we performed single cell RNA sequencing on CD19 + sorted cells from patients with MYD88 L265P versus MYD88 WT phenotype and compared them with two healthy controls.

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Effect of the FGFR kinase inhibitors AZD4547 and BGJ398 on gene expression in HaCaT cells

Project description:Fibroblast growth factors (FGF) play important roles during embryonic development as well as in the adult organism in tissue homeostasis, regeneration, repair and metabolism. We recently showed that inhibition of FGF receptor (FGFR) signaling in keratinocytes either pharmacologically or in a mouse FGFR1/2 knockout model, promoted expression of interferon-stimulated genes (ISGs) (Maddaluno et al, 2020). Here we analyzed the transcriptome of human HaCaT keratinocytes in response to treatment with the FGFR kinase inhibitors AZD4547 and BGJ398.

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Project description:The challenge of developing effective pharmacodynamic biomarkers for pre-clinical and clinical testing of FGFR signalling inhibition is significant. Assays that rely on the measurement of phospho-protein epitopes can be limited by the availability of effective antibody detection reagents. Transcript profiling enables accurate quantification of many biomarkers and a broader representation of pathway modulation. To identify dynamic transcript biomarkers of FGFR signalling inhibition by AZD4547, a potent inhibitor of FGF receptor 1, 2 and 3, a gene expression profiling study was performed in FGFR2 amplified drug sensitive tumour cell lines.

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Effect of FGF singaling inhibition on gene expression on limb bud mesenchyme explants.

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Aberrant extrafollicular B cells, immune dysfunction and myeloid inflammation precede malignancy in Waldenstrom macroglobulinemia

Project description:Waldenstrom macroglobulinemia (WM) and its precursor IgM gammopathy are distinct disorders characterized by the growth of mature IgM-expressing B cell clone predominantly in the bone marrow. Here we show that these disorders originate in the setting of expansion of genomically aberrant extrafollicular B cells, immune dysfunction and myeloid inflammation that begins before the expansion of the malignant clone. Host response to these early lesions involves the induction of tumor-specific T cell immunity that may include MYD88 mutation-specific responses. Hematopoietic progenitors carry the oncogenic MYD88 mutations characteristic of the malignant WM clone. These data provide an example of how oncogenic mutations in earlier progenitors may create the milieu promoting the evolution of malignant phenotype in differentiated cells.

2021-11-18 | GSE179221 | GEO

Gene expression changes caused by the IRAK1/IRAK4 inhibitor R191 in cell lines of Waldenström’s macroglobulinemia

Project description:The L265P mutation in MYD88 is very frequent in tumor cells of Waldenström’s macroglobulinemia (WM), and activates NF-kappaB through IRAK1 and IRAK4. We examined the effect of the IRAK1/4 inhibitor R191 on two cell lines of WM. Gene expression profiling suggested that R191 reduced activity of AKT and mTOR signaling, consistent with other assays and functional studies. Other changes suggested reduced proliferation and MYC activity, and an ER stress response.

2019-11-01 | GSE106409 | GEO

Translation cooperation of FGF and WNT signaling

Project description:Cooperation between FGF and WNT signaling is well documented in normal development, stem cell biology and cancer progression. However, the molecular mechanisms underlying this cooperativity remain poorly understood. In this study, we employed an inducible FGFR1 to interrogate the dynamics of RNA, ribosome occupancy and protein expression as a function of FGFR signaling in the mouse mammary gland with constitutive WNT hyperactivation. We demonstrate that FGFR signaling increases the translation efficiency of WNT signaling components with structured 5’ UTRs harboring a (CGG)4 motif that can potentially form G-quadruplex structures, and that tumorigenesis driven by this mechanism is vulnerable to inhibition of eIF4A, a RNA helicase important in translation initiation. This study also provides novel insights into the contribution of RNA levels and translational regulation to protein expression in pre-malignant mammary epithelial cells dynamically responding to FGFR signaling.

2018-05-29 | GSE107926 | GEO

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