Inhibiting MEK in MAPK pathway-activated myeloma

Heuck, Christoph; Jethava, Yogesh; Khan, Rashid Z; Rhee, Frits van; Zangari, Maurizio; Chavan, Shweta S.; Robbins, Kelly R.; Miller, Scott E.; Matin, Aasiya; Mohan, Meera; Ali, Siraj M.; Stephens, P. J.; Ross, Jeffrey S.; Miller, Vincent A.; Davies, Faith E.; Barlogie, Bart; Morgan, Gareth J.

doi:10.1038/leu.2015.208

Cited by 96 publications

(88 citation statements)

References 16 publications

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“…However, the activity of these agents has been variable in the clinical setting. A recent retrospective study reported significant anti-MM activity of a MEK inhibitor in patients with RAS and BRAF mutated tumors (44), whereas in a more recent prospective study there was little activity in relapsed/refractory patients (45). This later trial also included wild-type as well as mutant RAS and BRAF tumors, and it is possible that RAS mutations were limited to minor subclones that would limit efficacy against the entire tumor.…”

Section: Discussionmentioning

confidence: 99%

IQGAP1 Scaffold–MAP Kinase Interactions Enhance Multiple Myeloma Clonogenic Growth and Self-Renewal

Gocke

McMillan

Wang

et al. 2016

Molecular Cancer Therapeutics

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Despite improved outcomes in newly diagnosed multiple myeloma (MM), virtually all patients relapse and ultimately develop drug-resistant disease. Aberrant RAS/MAPK signaling is activated in the majority of relapsed/refractory MM patients, but its biological consequences are not fully understood. Self-renewal, as defined by the long-term maintenance of clonogenic growth, is essential for disease relapse and we examined the role of RAS/MAPK activation on MM self-renewal by targeting IQ motif–containing GTPase activating protein 1 (IQGAP1), an intracellular scaffold protein required for mutant RAS signaling. We found that loss of IQGAP1 expression decreased MAPK signaling, cell cycle progression, and tumor colony formation. Similarly, a peptide mimicking the WW domain of IQGAP1 that interacts with ERK inhibited the clonogenic growth and self-renewal of MM cell lines and primary clinical specimens in vitro as well as tumor initiating cell frequency in immunodeficient mice. During MM progression, self-renewal may be enhanced by aberrant RAS/MAPK signaling and inhibited by targeting IQGAP1.

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Section: Discussionmentioning

confidence: 99%

IQGAP1 Scaffold–MAP Kinase Interactions Enhance Multiple Myeloma Clonogenic Growth and Self-Renewal

Gocke

McMillan

Wang

et al. 2016

Molecular Cancer Therapeutics

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“…BRAF or MEK inhibitors are already in clinical testing and seem promising. 31,32,49,50 NRAS and KRAS mutations occurred mostly within known activating hotspots of the gene, and 4 of 9 BRAF mutations were druggable p.Val600Glu. However, BRAF mutations with paradoxical activation of the pathway via c-raf were also found in 4 patients, and in 1 of them (patient #41), 2 simultaneous BRAF mutations were identified: 1 at amino acid position 499 that has been suggested to be ERK activating and has been described in cardiofaciocutaneous syndrome, 51 and 1 in p.Glu695Lys, located in the protein kinase domain within the activator loop, previously reported in skin cutaneous melanoma.…”

Section: Discussionmentioning

confidence: 99%

Targeted sequencing of refractory myeloma reveals a high incidence of mutations in CRBN and Ras pathway genes

Kortüm

Elias

Hanafiah

et al. 2016

Blood

207

191

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• The incidence of mutations within the MAPK pathway, the CRBN pathway, and TP53 is significantly increased in drug-refractory MM.• Mutations in CRBN might contribute to IMiD resistance in drug-refractory MM.In this study, targeted sequencing to screen 50 multidrug refractory multiple myeloma (rMM) patients was performed by using the Multiple Myeloma Mutation Panel. Patients were pretreated with both immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs), and 88%, 78%, and 68% were refractory to an IMiD, a PI, or both, respectively. The majority of patients had progressive (82%) or refractory (78%) disease immediately before sampling, with 43% being IMiD refractory and 46% being PI refractory in the most recent line of therapy. Compared with newly diagnosed MM, an increased prevalence of mutations in the Ras pathway genes KRAS, NRAS, and/or BRAF (72%), as well as TP53 (26%), CRBN (12%), and CRBN pathway genes (10%) was observed. Longitudinal analyses performed in 3 patients with CRBN mutations at time of IMiD resistance confirmed that these mutations were undetectable at earlier, IMiD-sensitive time points. Furthermore, the functional introduction of these mutations in MM cells conferred lenalidomide resistance in vitro. These data indicate a differential genetic landscape in rMM associated with drug response. (Blood. 2016;128(9):1226-1233

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“…Results are based on small patient series and anecdotal reports with some patients experiencing remarkable responses to BRAF inhibition . Likewise, only few retrospective case series as well as in vitro and experimental in vivo data are available regarding mitogen‐activated protein kinase (MEK) inhibition as single agent therapy …”

Section: Introductionmentioning

confidence: 99%

Vemurafenib in combination with cobimetinib in relapsed and refractory extramedullary multiple myeloma harboring the BRAF V600E mutation

Mey

Renner²,

Moos

2016

Hematological Oncology

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BRAF mutations are present in a variety of cancers and cause constitutive activation of the Ras-Raf-MEK-ERK signaling pathway. In cutaneous malignant melanoma, combined treatment with BRAF and MEK inhibitors is associated with high response rates and has been shown to improve progression free as well as overall survival compared to BRAF inhibition alone. In multiple myeloma, BRAF mutations are detectable only in a minority of patients. Only few data are available regarding the clinical activity of BRAF inhibitors in BRAF-positive multiple myeloma patients, including some anecdotal reports on remarkable responses in individuals being resistant to all other available anti-myeloma treatment approaches. We here present the first report on the combination of vemurafenib and cobimetinib in a young patient with highly resistant and rapidly progressing multiple myeloma harboring the BRAF V600E mutation who achieved a rapid and sustained response to this combination therapy.

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Inhibiting MEK in MAPK pathway-activated myeloma

Cited by 96 publications

References 16 publications

IQGAP1 Scaffold–MAP Kinase Interactions Enhance Multiple Myeloma Clonogenic Growth and Self-Renewal

IQGAP1 Scaffold–MAP Kinase Interactions Enhance Multiple Myeloma Clonogenic Growth and Self-Renewal

Targeted sequencing of refractory myeloma reveals a high incidence of mutations in CRBN and Ras pathway genes

Vemurafenib in combination with cobimetinib in relapsed and refractory extramedullary multiple myeloma harboring the BRAF V600E mutation

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