Integrated phosphoproteomics and transcriptional classifiers reveal hidden RAS signaling dynamics in multiple myeloma

Lin, Yu-Hsiu T.; Way, Gregory P.; Barwick, Benjamin G.; Mariano, Margarette C.; Marcoulis, Makeba; Ferguson, Ian; Boise, Lawrence H.; Greene, Casey S.; Wiita, Arun P.

doi:10.1182/bloodadvances.2019000303

Cited by 21 publications

(18 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…KRAS-mutations did not have an influence on survival in bortezomib-treated patients at diagnosis. However, in contrast to the findings by an in silico analysis of the CoMMpass dataset [14], this was still evident after the separation into clonal and subclonal prevalence in our current dataset. Consistent with this finding, no association was observed with high-risk (e.g., del17p), intermediate-risk (e.g., t (4;14)), or standard-risk (e.g., t(11;14)) cytogenetic parameters.…”

Section: Discussioncontrasting

confidence: 99%

“…However, recently AMG 510-a covalently binding inhibitor of the p.G12C mutant of KRAS-was developed by leveraging the H95/Y96/Q99 cryptic pocket in GDP-KRASG12C, and has entered a phase 1/2 clinical trial (NCT03600883) after biopharmaceutical optimization [1]. The prognostic outcome of patients with RAS mutated MM has been assessed in several studies with contradicting conclusions, which may at least in part reflect the fact that different treatment regimens have been used [3,[12][13][14][15][16][17]. Of note, in trials treating relapsed/refractory patients with proteasome inhibitors, no significant difference in overall survival between RAS-mutant and RAS-WT patients was found [4,18].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Exon-4 Mutations in KRAS Affect MEK/ERK and PI3K/AKT Signaling in Human Multiple Myeloma Cell Lines

Weissbach

Heredia-Guerrero

Barnsteiner

et al. 2020

Cancers

View full text Add to dashboard Cite

Approximately 20% of multiple myeloma (MM) cases harbor a point mutation in KRAS. However, there is still no final consent on whether KRAS-mutations are associated with disease outcome. Specifically, no data exist on whether KRAS-mutations have an impact on survival of MM patients at diagnosis in the era of novel agents. Direct blockade of KRAS for therapeutic purposes is mostly impossible, but recently a mutation-specific covalent inhibitor targeting KRASp.G12C entered into clinical trials. However, other KRAS hotspot-mutations exist in MM patients, including the less common exon-4 mutations. For the current study, the coding regions of KRAS were deep-sequenced in 80 newly diagnosed MM patients, uniformely treated with three cycles of bortezomib plus dexamethasone and cyclophosphamide (VCD)-induction, followed by high-dose chemotherapy and autologous stem cell transplantation. Moreover, the functional impact of KRASp.G12A and the exon-4 mutations p.A146T and p.A146V on different survival pathways was investigated. Specifically, KRASWT, KRASp.G12A, KRASp.A146T, and KRASp.A146V were overexpressed in HEK293 cells and the KRASWT MM cell lines JJN3 and OPM2 using lentiviral transduction and the Sleeping Beauty vector system. Even though KRAS-mutations were not correlated with survival, all KRAS-mutants were found capable of potentially activating MEK/ERK- and sustaining PI3K/AKT-signaling in MM cells.

show abstract

Section: Discussioncontrasting

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Exon-4 Mutations in KRAS Affect MEK/ERK and PI3K/AKT Signaling in Human Multiple Myeloma Cell Lines

Weissbach

Heredia-Guerrero

Barnsteiner

et al. 2020

Cancers

View full text Add to dashboard Cite

show abstract

“…A secondary mutation that is uncommon in MGUS, KRAS, and NRAS mutations are each found in ~20% of NDMM patients ( 27 , 59 ). KRAS and NRAS mutations appear to not uniformly activate MAPK signaling pathways and actually lead to distinct downstream transcriptional signatures ( 60 ). Interestingly, FGFR3 mutations, which are mutually exclusive with RAS mutations appear to induce MAPK signaling more effectively ( 60 , 61 ).…”

Section: The Role Of the Bone Marrow Microenvironmentmentioning

confidence: 99%

“…KRAS and NRAS mutations appear to not uniformly activate MAPK signaling pathways and actually lead to distinct downstream transcriptional signatures ( 60 ). Interestingly, FGFR3 mutations, which are mutually exclusive with RAS mutations appear to induce MAPK signaling more effectively ( 60 , 61 ). Finally, the MAPK pathway can be activated by BRAF mutations.…”

Section: The Role Of the Bone Marrow Microenvironmentmentioning

confidence: 99%

Game of Bones: How Myeloma Manipulates Its Microenvironment

et al. 2021

Self Cite

View full text Add to dashboard Cite

Multiple myeloma is a clonal disease of long-lived plasma cells and is the second most common hematological cancer behind Non-Hodgkin’s Lymphoma. Malignant transformation of plasma cells imparts the ability to proliferate, causing harmful lesions in patients. In advanced stages myeloma cells become independent of their bone marrow microenvironment and form extramedullary disease. Plasma cells depend on a rich array of signals from neighboring cells within the bone marrow for survival which myeloma cells exploit for growth and proliferation. Recent evidence suggests, however, that both the myeloma cells and the microenvironment have undergone alterations as early as during precursor stages of the disease. There are no current therapies routinely used for treating myeloma in early stages, and while recent therapeutic efforts have improved patients’ median survival, most will eventually relapse. This is due to mutations in myeloma cells that not only allow them to utilize its bone marrow niche but also facilitate autocrine pro-survival signaling loops for further progression. This review will discuss the stages of myeloma cell progression and how myeloma cells progress within and outside of the bone marrow microenvironment.

show abstract

“…Deregulated activity of several kinases in MM cells, such as ERK, JUNK, STAT, MAPK, and AKT, indicates that phosphorylation pathways could be important for the disease physiopathology and clonal expansion [250][251][252][253]. Unbiased phosphoproteomics found differential activation of kinases that was linked to RAS mutations in different HMCLs, which allowed to build a predictive score linking pharmacologic and genetic kinase dependencies in MM [254]. Stable isotope labeling with amino acids in cell culture (SILAC) and liquid chromatography mass spectrometry (LC-MS)/MS analyses of primary MM cells treated with bortezomib identified novel bortezomib-induced phosphorylation sites, mostly in nucleic acid binding proteins, like splicing and translation factors [255].…”

Section: Proteomicsmentioning

confidence: 99%

Multi-omics tumor profiling technologies to develop precision medicine in multiple myeloma

Ovejero

Moreaux

2021

Exploration of Targeted Anti-Tumor Therapy

View full text Add to dashboard Cite

Multiple myeloma (MM), the second most common hematologic cancer, is caused by accumulation of aberrant plasma cells in the bone marrow. Its molecular causes are not fully understood and its great heterogeneity among patients complicates therapeutic decision-making. In the past decades, development of new therapies and drugs have significantly improved survival of MM patients. However, resistance to drugs and relapse remain the most common causes of mortality and are the major challenges to overcome. The advent of high throughput omics technologies capable of analyzing big amount of clinical and biological data has changed the way to diagnose and treat MM. Integration of omics data (gene mutations, gene expression, epigenetic information, and protein and metabolite levels) with clinical histories of thousands of patients allows to build scores to stratify the risk at diagnosis and predict the response to treatment, helping clinicians to make better educated decisions for each particular case. There is no doubt that the future of MM treatment relies on personalized therapies based on predictive models built from omics studies. This review summarizes the current treatments and the use of omics technologies in MM, and their importance in the implementation of personalized medicine.

show abstract

Integrated phosphoproteomics and transcriptional classifiers reveal hidden RAS signaling dynamics in multiple myeloma

Abstract: Key Points NRAS and KRAS mutations lead to different downstream transcriptional signatures and patient prognoses under current myeloma therapies. RAS genotype alone does not strongly predict degree of active MAPK signaling, suggesting alternate precision medicine approaches are needed.

Cited by 21 publications

References 51 publications

Exon-4 Mutations in KRAS Affect MEK/ERK and PI3K/AKT Signaling in Human Multiple Myeloma Cell Lines

Exon-4 Mutations in KRAS Affect MEK/ERK and PI3K/AKT Signaling in Human Multiple Myeloma Cell Lines

Game of Bones: How Myeloma Manipulates Its Microenvironment

Multi-omics tumor profiling technologies to develop precision medicine in multiple myeloma

Contact Info

Product

Resources

About