Mutation of NRAS but not KRAS significantly reduces myeloma sensitivity to single-agent bortezomib therapy

Mulligan, George; Lichter, David I.; Bacco, Alessandra Di; Blakemore, Stephen J.; Berger, Allison; Koenig, Erik; Bernard, Hugues; Trepicchio, William L.; Li, Bin; Neuwirth, Rachel; Chattopadhyay, Nibedita; Bolen, Joseph B.; Dorner, Andrew J.; Velde, Helgi van de; Ricci, Deborah; Jagannath, Sundar; Berenson, James R.; Richardson, Paul G.; Stadtmauer, Edward A.; Orłowski, Robert Z.; Lonial, Sagar; Anderson, Kenneth C.; Sonneveld, Pieter; Miguel, Jesús F. San; Esseltine, Dixie Lee; Schu, Matthew

doi:10.1182/blood-2013-05-504340

Cited by 109 publications

(116 citation statements)

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“…In MM, the proportion of RAS mutations increases with disease progression, and 46 - 81% of patients with relapsed disease have been found to have N- or K-RAS mutations (25, 26). Recently, a study evaluating the prevalence of RAS mutations in MM patient samples from 133 patients demonstrated N- and K-RAS mutations in similar proportions, and patients with N-RAS mutated tumors, in comparison to those with wild-type tumors, were less sensitive to bortezomib (27). The mechanisms underlying this decreased bortezomib sensitivity of N-RAS mutated tumors require further investigation.…”

Section: Discussionmentioning

confidence: 99%

A Phase I Trial of Single-Agent Reolysin in Patients with Relapsed Multiple Myeloma

Sborov

Nuovo

Stiff

et al. 2014

Clinical Cancer Research

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Introduction Reolysin®, a proprietary isolate of reovirus Type 3 Dearing, enters and preferentially induces apoptosis of malignant cells. RAS pathway activation has been associated with more efficient reoviral infectivity and enhanced oncolysis. Reovirus is currently in advanced solid tumor phase 1 – 2 trials; no clinical trials have been conducted in patients with hematologic malignancies. Methodologies A phase 1 trial treated 12 relapsed myeloma patients at two dose levels. Reolysin was infused daily for 5 days every 28 days. Bone marrow specimens were examined by In situ based hybridization (ISH) for CD138, p38, caspase-3, reoviral RNA and capsid protein at screening and cycle 1 day 8. Junctional adhesion molecule 1 (JAM-1) and cancer up regulated gene 2 (CUG2) were evaluated in patient samples and MM cell lines. Neutralizing Anti-Reovirus Antibody (NARA) assay was performed weekly during cycle 1. Results There were no dose limiting toxicities (DLTs), patients reached the 3 x 1010 TCID50 daily on days 1-5 dose level, and grade 3 laboratory toxicities included neutropenia, thrombocytopenia, and hypophosphatemia. In situ hybridization demonstrated reoviral genome confined in MM cells. Reoviral capsid protein and caspase-3 were rarely identified within reoviral RNA positive cells. The longest durations of stable disease were 4, 5 and 8 months. Conclusions Treatment with single-agent Reolysin was well tolerated and associated with avid reoviral RNA myeloma cell entry but only minimal intracellular reoviral protein production within MM cells. Our data support that in MM cells, Reolysin-induced oncolysis requires combination therapy, similar to other cancers.

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Section: Discussionmentioning

confidence: 99%

A Phase I Trial of Single-Agent Reolysin in Patients with Relapsed Multiple Myeloma

Sborov

Nuovo

Stiff

et al. 2014

Clinical Cancer Research

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“…Mutations in these genes have been shown to drive Wnt signaling in other tumors (17)(18)(19); however, the effect of these specific mutations on Wnt signaling in MM remains to be established. In addition, in analyzing the data of Mulligan et al (44) involving targeted sequencing of established oncogenes, we identified a T41I mutation in β-catenin (CTNNB1) and a frameshift mutation in APC (S1465fs*3), both of which have been shown to drive oncogenic Wnt signaling (45,46). Thus, these mutations might represent alternative mechanisms driving Wnt signaling in a subset of MMs.…”

Section: Discussionmentioning

confidence: 99%

Aberrantly expressed LGR4 empowers Wnt signaling in multiple myeloma by hijacking osteoblast-derived R-spondins

Andel

Ren

Koopmans

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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The unrestrained growth of tumor cells is generally attributed to mutations in essential growth control genes, but tumor cells are also affected by, or even addicted to, signals from the microenvironment. As therapeutic targets, these extrinsic signals may be equally significant as mutated oncogenes. In multiple myeloma (MM), a plasma cell malignancy, most tumors display hallmarks of active Wnt signaling but lack activating Wnt-pathway mutations, suggesting activation by autocrine Wnt ligands and/or paracrine Wnts emanating from the bone marrow (BM) niche. Here, we report a pivotal role for the R-spondin/leucine-rich repeat-containing G protein-coupled receptor 4 (LGR4) axis in driving aberrant Wnt/ β-catenin signaling in MM. We show that LGR4 is expressed by MM plasma cells, but not by normal plasma cells or B cells. This aberrant LGR4 expression is driven by IL-6/STAT3 signaling and allows MM cells to hijack R-spondins produced by (pre)osteoblasts in the BM niche, resulting in Wnt (co)receptor stabilization and a dramatically increased sensitivity to auto-and paracrine Wnts. Our study identifies aberrant R-spondin/LGR4 signaling with consequent deregulation of Wnt (co)receptor turnover as a driver of oncogenic Wnt/ β-catenin signaling in MM cells. These results advocate targeting of the LGR4/R-spondin interaction as a therapeutic strategy in MM.M ultiple myeloma (MM) in most patients is an incurable hematologic malignancy characterized by the accumulation of clonal plasma cells in the bone marrow (BM). Despite the wide variety of underlying structural and numerical genomic abnormalities (1-3), virtually all MMs are highly dependent on a protective BM microenvironment, or "niche," for growth and survival (4). Understanding the complex reciprocal interaction between MM cells and the BM microenvironment is critical for the development of new targeted therapies.In MM, aberrant activation of the canonical Wnt pathway drives proliferation and is associated with disease progression, dissemination, and drug resistance (5-9). Because MMs with hallmarks of active Wnt signaling do not harbor mutations that typically underlie constitutive Wnt pathway activation, this oncogenic Wnt pathway activity was proposed to involve autocrine and/or paracrine Wnt ligands (6,8,10). Wnts are lipid-modified glycoproteins that function as typical niche factors because they are relatively unstable and insoluble due to their hydrophobic nature, which constrains long-range signaling (11). Binding of a Wnt ligand to its receptor Frizzled (Fzd) initiates a signaling cascade that ultimately results in stabilization and nuclear translocation of the Wnt effector β-catenin. In cooperation with TCF/LEF family transcription factors this orchestrates a transcriptional program (12, 13), comprising targets such as MYC and CCND1 (Cyclin D1) that play crucial roles in the pathogenesis of MM (14-16). Aberrant Wnt signaling in cancer typically results from mutations in APC, β-catenin (CTNNB1), or AXIN that drive constitutive, ligand-independent pathway ac...

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“…Activating RAS mutations are considered to be molecular markers of disease progression. 5 Therefore, the prevalence of activating KRAS and NRAS mutations is Ͼ70% in MM cases at relapse. TP53 inactivation via deletion or mutation also seems to be more frequently associated with disease progression.…”

Section: Genomic Characteristics Of Myeloma Cellsmentioning

confidence: 99%

Multiple myeloma: a model for scientific and clinical progress

Miguel

2014

Hematology

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Multiple myeloma (MM) is a unique cancer paradigm for investigating the mechanisms involved in the transition from a premalignant condition (monoclonal gammopathy of undetermined significance) into a malignant disease (MM). In the pathogenesis of myeloma, the dialogue between plasma cells and their microenvironment is as important as the genotypic characteristics of the tumor clone. MM is genetically highly complex, with almost all patients displaying cytogenetic abnormalities and frequent intraclonal heterogeneity that play a critical role in the outcome of the disease. In fact, it is likely that myeloma will soon no longer be considered as a single entity. This, along with the availability of an unexpected number of new treatment possibilities, has reinforced the need for better tools for prognosis and for monitoring treatment efficacy through minimal residual disease techniques. The outcome of MM patients has significantly improved in the last 2 decades, first through the introduction of high-dose therapy followed by autologous stem cell transplantation and, more recently, due to the use of proteasome inhibitors (bortezomib and carfilzomib) and immunomodulatory agents (thalidomide, lenalidomide, and pomalidomide). Moreover, the need to reexamine the diagnostic criteria of early MM and the possibility of early intervention opens up new therapeutic avenues. New drugs are also emerging, including second-and third-generation proteasome inhibitors and immunomodulators, monoclonal antibodies, histone deacetylase inhibitors, and kinesin spindle protein inhibitors, among others. Our goal is to find a balance among efficacy, toxicity, and cost, with the ultimate aim of achieving a cure for this disease. Learning Objectives• To understand that myeloma should no longer be considered as a single entity • To understand that better tools for diagnosis and monitoring treatment efficacy are being implemented • To understand that the treatment goal is to find the best possible balance among efficacy, toxicity, and cost

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Mutation of NRAS but not KRAS significantly reduces myeloma sensitivity to single-agent bortezomib therapy

Cited by 109 publications

References 43 publications

A Phase I Trial of Single-Agent Reolysin in Patients with Relapsed Multiple Myeloma

A Phase I Trial of Single-Agent Reolysin in Patients with Relapsed Multiple Myeloma

Aberrantly expressed LGR4 empowers Wnt signaling in multiple myeloma by hijacking osteoblast-derived R-spondins

Multiple myeloma: a model for scientific and clinical progress

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